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Wu JC, Cheng HX, Lan QS, Xu HY, Zeng YJ, Lai W, Chu ZH. Penile metastasis from colon cancer with BRAFV600E mutation treated with BRAF/MEK-targeted therapy plus cetuximab: A case report. World J Gastrointest Oncol 2025; 17:100152. [DOI: 10.4251/wjgo.v17.i3.100152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 11/03/2024] [Accepted: 12/13/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND The incidence of colon cancer has been progressively increasing over time, whereas penile metastasis of colon cancer has remained exceedingly uncommon. Since the prognosis for colon cancer with BRAFV600E mutation is relatively unfavorable, further exploration and investigation are still required to develop treatment strategies for such rare cases.
CASE SUMMARY About one year after surgery and chemotherapy, a 50-year-old patient with sigmoid colon cancer developed a mass at the base of the patient's penis, accompanied by severe tenderness and pain during urination. With disease progression, multiple metastatic nodules also emerged in other regions of the penis, including the coronal sulcus. The nodules located in the coronal sulcus were excised for histopathological examination. The histopathological findings revealed that the nodules were metastases originating from the sigmoid colon cancer, with a BRAFV600E mutation detected. This prompted a modification of the therapy regimen of cetuximab, dabrafenib and trametinib, which effectively held back the progression of penile metastasis in the patient.
CONCLUSION Combining the BRAF/MEK-targeted therapy with cetuximab demonstrates a favorable therapeutic response in BRAFV600E-mutated colon cancer with penile metastasis.
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Affiliation(s)
- Jun-Chen Wu
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Hua-Xi Cheng
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Qiu-Sheng Lan
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - He-Yang Xu
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Yu-Jie Zeng
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Wei Lai
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Zhong-Hua Chu
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
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Napolitano S, Ciardiello D, Cioli E, Martinelli E, Troiani T, Giulia Zampino M, Fazio N, De Vita F, Ciardiello F, Martini G. BRAFV600E mutant metastatic colorectal cancer: Current advances in personalized treatment and future perspectives. Cancer Treat Rev 2025; 134:102905. [PMID: 40009904 DOI: 10.1016/j.ctrv.2025.102905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 02/19/2025] [Accepted: 02/19/2025] [Indexed: 02/28/2025]
Abstract
Detection of the BRAF V600E mutation has important genetic, prognostic, and therapeutic implications for patients with metastatic colorectal cancer (mCRC), identifying a subgroup of patients who derive modest benefit from standard treatments and have extremely poor prognosis. The evolution of molecular profiling and the implementation of next generation sequencing in the evaluation of a patient with BRAF-mutated mCRC has currently led to the discovery of actionable alterations. Targeting multiple pathways of resistance in BRAF-mutated mCRC may be the most efficacious route. Then, over a short period of time, the treatment landscape BRAF-mutated mCRC patients has shifted dramatically. Finally, novel treatment strategies are available. This review will discuss on currently approved treatments for BRAF V600E mutated mCRC and will try and portray the changing landscape in this setting in the era of targeted molecular therapy.
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Affiliation(s)
- Stefania Napolitano
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy.
| | - Davide Ciardiello
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Eleonora Cioli
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Erika Martinelli
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Teresa Troiani
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Maria Giulia Zampino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Ferdinando De Vita
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Fortunato Ciardiello
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giulia Martini
- Department of Precision Medicine, The University of Campania Luigi Vanvitelli, Naples, Italy
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3
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Piercey O, Chantrill L, Hsu H, Ma B, Price T, Tan IB, Teng H, Tie J, Desai J. Expert consensus on the optimal management of BRAF V600E-mutant metastatic colorectal cancer in the Asia-Pacific region. Asia Pac J Clin Oncol 2025; 21:31-45. [PMID: 39456063 PMCID: PMC11733838 DOI: 10.1111/ajco.14132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 09/14/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024]
Abstract
The burden of colorectal cancer (CRC) is high in the Asia-Pacific region, and several countries in this region have among the highest and/or fastest growing rates of CRC in the world. A significant proportion of patients will present with or develop metastatic CRC (mCRC), and BRAFV600E-mutant mCRC represents a particularly aggressive phenotype that is less responsive to standard chemotherapies. In light of recent therapeutic advances, an Asia-Pacific expert consensus panel was convened to develop evidence-based recommendations for the diagnosis, treatment, and management of patients with BRAFV600E-mutant mCRC. The expert panel comprised nine medical oncologists from Australia, Hong Kong, Singapore, and Taiwan (the authors), who met to review current literature and develop eight consensus statements that describe the optimal management of BRAFV600E-mutant mCRC in the Asia-Pacific region. As agreed by the expert panel, the consensus statements recommend molecular testing at diagnosis to guide individualized treatment decisions, propose optimal treatment pathways according to microsatellite stability status, advocate for more frequent monitoring of BRAFV600E-mutant mCRC, and discuss local treatment strategies for oligometastatic disease. Together, these expert consensus statements are intended to optimize treatment and improve outcomes for patients with BRAFV600E-mutant mCRC in the Asia-Pacific region.
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Affiliation(s)
| | - Lorraine Chantrill
- Illawarra Shoalhaven Local Health DistrictIllawarraNew South WalesAustralia
- Faculty of Science, Medicine and HealthUniversity of WollongongWollongongNew South WalesAustralia
| | - Hung‐Chih Hsu
- Division of Hematology OncologyChang Gung Memorial HospitalNew TaipeiTaiwan
- College of MedicineChang Gung UniversityTaoyuanTaiwan
| | - Brigette Ma
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer InstituteThe Chinese University of Hong KongHong Kong SARChina
| | - Timothy Price
- The Queen Elizabeth HospitalAdelaideSouth AustraliaAustralia
| | - Iain Beehuat Tan
- Division of Medical OncologyNational Cancer Centre SingaporeSingaporeSingapore
| | - Hao‐Wei Teng
- Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
| | - Jeanne Tie
- Peter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVictoriaAustralia
| | - Jayesh Desai
- Peter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVictoriaAustralia
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4
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Taniguchi H, Uehara K, Ishikawa T, Okochi O, Akazawa N, Okuda H, Hasegawa H, Shiozawa M, Kataoka M, Satake H, Shimura T, Kondoh C, Kuramochi H, Matsumoto T, Takegawa N, Yamaguchi T, Nagase M, Nakamura M, Takano N, Fujita H, Watanabe T, Nishina T, Sakamoto Y, Moriwaki T, Ohori H, Nakanishi M, Kito Y, Utsunomiya S, Ishikawa T, Manaka D, Matsuoka H, Suto T, Arai T, Shinzaki S, Funakoshi T, Nakayama G, Negoro Y, Tsuji Y, Makiyama A, Takuma K, Arimoto A, Shinozaki K, Mishima A, Masuishi T. BRAF V600E and Non-V600E Mutations in RAS Wild-Type Metastatic Colorectal Cancer: Prognostic and Therapeutic Insights from a Nationwide, Multicenter, Observational Study (J-BROS). Cancers (Basel) 2025; 17:399. [PMID: 39941768 PMCID: PMC11815755 DOI: 10.3390/cancers17030399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES BRAF mutations occur in 5-10% of metastatic colorectal cancer (mCRC) cases, but their implications for prognosis and optimal treatment remain unclear. METHODS This multicenter, prospective observational study analyzed 377 RAS wild-type cases from 511 patients across 32 centers, using PCR-based methods. RESULTS BRAF mutations were identified in 21% (79/377) of cases, predominantly V600E (89.9%) with a minority of non-V600E (10.1%). Microsatellite instability (MSI) testing revealed MSI-high in 11.3%, exclusively among V600E cases. V600E mutations were linked to right-sided tumors, poor differentiation, and elevated CA19-9 levels. Median survival was significantly lower in V600E cases compared to BRAF wild-type (12.4 vs. 37.5 months, HR 3.25, p < 0.001) and marginally lower non-V600E cases (12.4 vs. 34.7 months, HR 0.61, p = 0.057). Chemotherapy regimens (doublet vs. triplet) and targeted treatments (bevacizumab vs. anti-EGFR) showed no significant survival differences in V600E patients. Similarly, RAS/BRAF wild-type patients had comparable survival with bevacizumab versus anti-EGFR, even for left-sided tumors. CONCLUSIONS These findings highlight distinct clinical and prognostic profiles for BRAF V600E and non-V600E mutations, while treatment choice appears to have limited impact on survival in these subgroups or RAS/BRAF wild-type cases.
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Affiliation(s)
- Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Kay Uehara
- Department of Gastroenterological Surgery, Nagoya University Hospital, Nagoya 466-8560, Japan
- Department of Gastroenterological Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Toshiaki Ishikawa
- Department of Specialized Surgeries, Institute of Science Tokyo, Tokyo 113-8519, Japan
- Department of Medical Oncology, Juntendo University, Tokyo 113-8431, Japan
| | - Osamu Okochi
- Department of Surgery, Tosei General Hospital, Seto 489-8642, Japan
| | - Naoya Akazawa
- Department of Gastroenterological Surgery, Sendai City Medical Center Sendai Open Hospital, Sendai 983-0824, Japan
| | - Hiroyuki Okuda
- Department of Clinical Oncology, Keiyukai Sapporo Hospital, Sapporo 003-0026, Japan
| | - Hiroko Hasegawa
- Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka 540-0006, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama 241-0815, Japan
| | - Masato Kataoka
- Department of Surgery, NHO Nagoya Medical Center, Nagoya 460-0001, Japan
| | - Hironaga Satake
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan
- Department of Medical Oncology, Kochi Medical School, Nankoku 783-8505, Japan
| | - Takaya Shimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8602, Japan
| | - Chihiro Kondoh
- Department of Medical Oncology, Toranomon Hospital, Tokyo 105-8470, Japan
- Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - Hidekazu Kuramochi
- Department of Chemotherapy, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo 276-8524, Japan
- Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan
| | - Toshihiko Matsumoto
- Department of Internal medicine, Himeji Red Cross Hospital, Himeji 670-8540, Japan
- Department of Medical Oncology, Ichinomiyanishi Hospital, Ichinomiya 494-0001, Japan
| | - Naoki Takegawa
- Department of Gastroenterology, Hyogo Cancer Center, Akashi 673-8558, Japan
| | - Toshifumi Yamaguchi
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki 569-0801, Japan
| | - Michitaka Nagase
- Department of Medical Oncology, Saku Central Hospital Advanced Care Center, Saku 385-0051, Japan
| | - Masato Nakamura
- Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto 390-8510, Japan
| | - Nao Takano
- Department of Surgery, Tokai Central Hospital, Kagamihara 504-8601, Japan
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya 466-8560, Japan
| | - Hideto Fujita
- Department of General and Digestive surgery, Kanazawa Medical University, Uchinadamachi 920-0293, Japan
| | - Takanori Watanabe
- Department of Surgery, Japanese Red Cross Society Himeji Hospital, Himeji 670-8540, Japan
- Department of Surgery, Tokushima Municipal Hospital, Tokushima 770-0812, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama 791-0245, Japan
| | - Yasuhiro Sakamoto
- Department of Medical Oncology, Osaki Citizen Hospital, Osaki 989-6183, Japan
| | - Toshikazu Moriwaki
- Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8576, Japan
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki 710-8602, Japan
| | - Hisatsugu Ohori
- Department of Medical Oncology, Ishinomaki Red Cross Hospital, Ishinomaki 986-8522, Japan
| | - Masayoshi Nakanishi
- Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
- Department of Surgery, Matsushita Memorial Hospital, Moriguchi 570-8540, Japan
| | - Yosuke Kito
- Department of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa 920-8530, Japan
| | - Setsuo Utsunomiya
- Department of Clinical Oncology, Kainan Hospital, Yatomi 498-8502, Japan
| | - Takeshi Ishikawa
- Outpatient Oncology Unit, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Dai Manaka
- Department of Surgery, Kyoto Katsura Hospital, Kyoto 615-8256, Japan
| | - Hiroshi Matsuoka
- Department of Surgery, Fujita Health University, Toyoake 470-1192, Japan
| | - Takeshi Suto
- Department of Gastroenterological Surgery, Yamagata Prefectural Central Hospital, Yamagata 990-2292, Japan
| | - Toshiyuki Arai
- Department of Surgery, Anjo Kosei Hospital, Anjo 446-8602, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology, School of Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Tohru Funakoshi
- Department of Surgery, Asahikawa Kosei General Hospital, Asahikawa 078-8211, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
| | - Yuji Negoro
- Department of Oncological Medicine, Kochi Health Sciences Center, Kochi 781-8555, Japan
| | - Yasushi Tsuji
- Department of Medical Oncology, Tonan Hospital, Sapporo 060-0004, Japan
| | - Akitaka Makiyama
- Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushyu 806-0034, Japan
- Cancer Center, Gifu University Hospital, Gifu 501-1194, Japan
| | - Kunio Takuma
- Department of Surgery, Tokyo Metropolitan Tama Medical Center, Fuchu 183-8524, Japan
| | - Atsuki Arimoto
- Department of General Surgery, Toyohashi Municipal Hospital, Toyohashi 441-8570, Japan
| | - Katsunori Shinozaki
- Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima 734-8530, Japan
| | - Ayako Mishima
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
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Kopetz S, Yoshino T, Van Cutsem E, Eng C, Kim TW, Wasan HS, Desai J, Ciardiello F, Yaeger R, Maughan TS, Beyzarov E, Zhang X, Ferrier G, Zhang X, Tabernero J. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med 2025:10.1038/s41591-024-03443-3. [PMID: 39863775 DOI: 10.1038/s41591-024-03443-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/03/2024] [Indexed: 01/27/2025]
Abstract
Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, 2.443; 95% confidence interval (CI): 1.403-4.253; 99.8% CI: 1.019-5.855; one-sided P = 0.0008). Median duration of response was 13.9 versus 11.1 months. At this first interim analysis of overall survival, the hazard ratio was 0.47 (95% CI: 0.318-0.691; repeated CI: 0.166-1.322). Serious adverse event rates were 37.7% versus 34.6%. The safety profiles were consistent with those known for each agent. BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC+mFOLFOX6 versus SOC in patients with BRAF V600E mCRC. ClinicalTrials.gov identifier: NCT04607421 .
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Affiliation(s)
- Scott Kopetz
- University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | | | - Eric Van Cutsem
- University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - Cathy Eng
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Tae Won Kim
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Jayesh Desai
- Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, VIC, Australia
| | | | - Rona Yaeger
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | | | | | | | | | - Josep Tabernero
- Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), University of Vic - Central University of Catalonia, Barcelona, Spain
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Sun Z, Shi M, Xia J, Li X, Chen N, Wang H, Gao Z, Jia J, Yang P, Ji D, Gu J. HDAC and MEK inhibition synergistically suppresses HOXC6 and enhances PD-1 blockade efficacy in BRAF V600E-mutant microsatellite stable colorectal cancer. J Immunother Cancer 2025; 13:e010460. [PMID: 39800382 PMCID: PMC11749543 DOI: 10.1136/jitc-2024-010460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 12/06/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND B-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E-mutant microsatellite stable (MSS) colorectal cancer (CRC) constitutes a distinct CRC subgroup, traditionally perceived as minimally responsive to standard therapies. Recent clinical attempts, such as BRAF inhibitors (BRAFi) monotherapy and combining BRAFi with other inhibitors, have yielded unsatisfactory efficacy. This study aims to identify a novel therapeutic strategy for this challenging subgroup. METHODS We first performed a large-scale drug screening using patient-derived organoid models and cell lines to pinpoint potential therapies. Subsequently, we investigated the synergistic effects of identified effective inhibitors and probed their cooperative mechanisms. Concurrently, we explored the immune characteristics of BRAFV600E MSS CRC using RNA sequencing and multiplex immunohistochemistry. Finally, we established a CT26 BRAFV637E mouse cell line and validated the efficacy of combining these inhibitors and programmed death 1 (PD-1) blockades in immunocompetent mice. RESULTS Drug screening identified histone deacetylase (HDAC) inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor as significantly effective against BRAFV600E MSS CRC. Further research revealed that these two inhibitors have superior synergistic effects by comprehensively inhibiting the activation of the epidermal growth factor receptor, mitogen-activated protein kinase, and phosphoinositide 3-kinase-protein kinase B pathways and suppressing the key target homeobox C6 (HOXC6). HOXC6, overexpressed in BRAFV600E MSS CRC, regulates the MYC gene and contributes to treatment resistance, tumor growth, and metastasis. Moreover, the combination therapy demonstrated the ability to enhance antitumor immunity by synergistically upregulating the expression of immune activation-related genes, activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway, and diminishing the tumor cells' DNA mismatch repair capacity. Notably, BRAFV600E MSS CRC was identified to exhibit a distinct immune microenvironment with increased PD-1+ cell infiltration and potential responsiveness to immunotherapy. Echoing the above findings, in vivo, HDAC and MEK inhibitors significantly improved PD-1 blockade efficacy, accompanied by increased CD8+ T-cell infiltration. CONCLUSIONS Our findings indicate that combining HDAC inhibitor, MEK inhibitor, and PD-1 blockade is a potential strategy for treating BRAFV600E-mutant MSS CRC, warranting further investigation in clinical settings.
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Affiliation(s)
- Zhuang Sun
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Mengyuan Shi
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jinhong Xia
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xin Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Nan Chen
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hanyang Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhaoya Gao
- Peking University Shougang Hospital, Beijing, China
| | - Jinying Jia
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Peng Yang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Dengbo Ji
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jin Gu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
- Peking University Shougang Hospital, Beijing, China
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7
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Adashek JJ, Munoz JL, Kurzrock R. If it is a solid tumor target, then it may be a hematologic cancer target: Bridging the great divide. MED 2025; 6:100550. [PMID: 39689708 PMCID: PMC11725447 DOI: 10.1016/j.medj.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 10/01/2024] [Accepted: 11/01/2024] [Indexed: 12/19/2024]
Abstract
Tumor-agnostic US Food and Drug Administration approvals are transforming oncology. They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAFV600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms. The genomically driven tissue-agnostic approach has a strong biological rationale (cancer is a disease of the genome), yields remarkably high response rates, and provides drug access to patients with an unmet need (rare/ultra-rare malignancies). Despite the solid tumor focus, both solid and hematologic cancers can harbor identical driver molecular abnormalities and respond to cognate therapies. For example, BRAFV600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor T cells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers.
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Affiliation(s)
- Jacob J Adashek
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Javier L Munoz
- Department of Hematology, Mayo Clinic Arizona, Phoenix, AZ, USA.
| | - Razelle Kurzrock
- Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; WIN Consortium, Paris, France; University of Nebraska, Omaha, NE, USA.
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8
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Qu F, Wu S, Yu W. Progress of Immune Checkpoint Inhibitors Therapy for pMMR/MSS Metastatic Colorectal Cancer. Onco Targets Ther 2024; 17:1223-1253. [PMID: 39735789 PMCID: PMC11681808 DOI: 10.2147/ott.s500281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/12/2024] [Indexed: 12/31/2024] Open
Abstract
Immunotherapy is one of the research hotspots in colorectal cancer field in recent years. The colorectal cancer patients with mismatch repair-deficient (dMMR) or high microsatellite instability (MSI-H) are the primary beneficiaries of immunotherapy. However, the vast majority of colorectal cancers are mismatch repair proficient (pMMR) or microsatellite stability (MSS), and their immune microenvironment is characterized by "cold tumors" that are generally insensitive to single immunotherapy based on immune checkpoint inhibitors (ICIs). Studies have shown that some pMMR/MSS colorectal cancer patients regulate the immune microenvironment by combining other treatments, such as multi-target tyrosine kinase inhibitors, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, chemotherapy, radiotherapy, anti-epithelial growth factor receptor (EGFR) monoclonal antibodies, and mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and oncolytic viruses, etc. to transform "cold tumor" into "hot tumor", thereby improving the response to immunotherapy. In addition, screening for potential prognostic biomarkers can also enrich the population benefiting from immunotherapy for microsatellite stable colorectal cancer. Therefore, in pMMR or MSS metastatic colorectal cancer (mCRC), the optimization of immunotherapy regimens and the search for effective efficacy prediction biomarkers are currently important research directions. In this paper, we review the progress of efficacy of immunotherapy (mainly ICIs) in pMMR /MSS mCRC, challenges and potential markers, in order to provide research ideas for the development of immunotherapy for mCRC.
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Affiliation(s)
- Fanjie Qu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
| | - Shuang Wu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
| | - WeiWei Yu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
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9
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Simhadri S, Carrick JN, Murphy S, Kothari OA, Al-Hraishami H, Kulkarni A, Jalloul N, Stefanik K, Bandari M, Chettur K, Yao M, Ginjala V, Groisberg R, Hochster H, Mehnert J, Riedlinger G, Khiabanian H, Verzi MP, Tong K, Ganesan S. Evolution of Rapid Clonal Dynamics and Non-Cross-Resistance in Response to Alternating Targeted Therapy and Chemotherapy in BRAF-V600E-Mutant Colon Cancer. JCO Precis Oncol 2024; 8:e2300260. [PMID: 39626159 PMCID: PMC11627326 DOI: 10.1200/po.23.00260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/28/2024] [Accepted: 09/27/2024] [Indexed: 12/11/2024] Open
Abstract
PURPOSE Combined BRAF, MEK, and EGFR inhibition can induce clinical responses in BRAF-V600E-mutant colon cancer, but rapid resistance often occurs. METHODS We use serial monitoring of circulating tumor DNA cell-free plasma DNA (cfDNA) in a patient case study in addition to organoids derived from mouse models of BRAF-V600E-mutant intestinal cancer, which emulated the patient's mutational profile to assess drug treatment efficacy. RESULTS We demonstrate dynamic evolution of resistance to combined EGFR/BRAF/MEK inhibition in a pediatric patient with metastatic BRAF-V600E-mutant, mismatch repair-stable colon cancer. Initial resistance to targeted therapy was associated with development of MET amplification. Sequential treatment with chemotherapy and targeted therapy resulted in clearing of the resistant MET-amplified clone. Rechallenge with combined BRAF/EGFR inhibition resulted in clinical and radiographic response, demonstrating these treatments may be non-cross-resistant. Tumor organoids were used to model clinical findings and demonstrated effectiveness of combined targeted therapy and chemotherapy. CONCLUSION These findings suggest rational strategies for combining sequential chemotherapy and BRAF-/EGFR-directed therapy in BRAF-V600E-mutant colon cancer to prevent resistance and improve outcome. The data demonstrate rapid clonal dynamics in response to effective therapies in BRAF-V600E-mutant colon cancer that can be monitored by serial cfDNA analysis. Moreover, in mismatch repair-proficient BRAF-V600E-mutant colon cancers, combined EGFR and BRAF/MEK therapy is not cross-resistant with standard chemotherapy, suggesting new rational combination treatment strategies.
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Affiliation(s)
- Srilatha Simhadri
- Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Jillian N. Carrick
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway Township, NJ
- Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ
| | - Susan Murphy
- Department of Medicine, Pediatric Hematology/Oncology Program, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Om A. Kothari
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway Township, NJ
| | - Husam Al-Hraishami
- Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Atul Kulkarni
- Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Nahed Jalloul
- Department of Pathology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Katarina Stefanik
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway Township, NJ
- Department of Biology, The College of New Jersey, Ewing, NJ
| | - Manisha Bandari
- Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ
| | - Kavya Chettur
- Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ
- Tenafly High School, Tenafly, NJ
| | - Ming Yao
- Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Vasudeva Ginjala
- Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Roman Groisberg
- Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Howard Hochster
- Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Janice Mehnert
- Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Gregory Riedlinger
- Department of Pathology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Hossein Khiabanian
- Department of Pathology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Michael P. Verzi
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway Township, NJ
| | - Kevin Tong
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway Township, NJ
- Department of Biology, The College of New Jersey, Ewing, NJ
- Department of Medical Sciences, Hackensack Meridian Health School of Medicine, Nutley, NJ
| | - Shridar Ganesan
- Department of Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
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10
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Liu M, Liu Q, Hu K, Dong Y, Sun X, Zou Z, Ji D, Liu T, Yu Y. Colorectal cancer with BRAF V600E mutation: Trends in immune checkpoint inhibitor treatment. Crit Rev Oncol Hematol 2024; 204:104497. [PMID: 39245296 DOI: 10.1016/j.critrevonc.2024.104497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 08/29/2024] [Accepted: 08/31/2024] [Indexed: 09/10/2024] Open
Abstract
Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC.
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Affiliation(s)
- Mengling Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qing Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Keshu Hu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yu Dong
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xun Sun
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhiguo Zou
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Dingkun Ji
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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11
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Wang W, Lian B, Xu C, Wang Q, Li Z, Zheng N, Liu A, Yu J, Zhong W, Wang Z, Zhang Y, Liu J, Zhang S, Cai X, Liu A, Li W, Mao L, Zhan P, Liu H, Lv T, Miao L, Min L, Chen Y, Yuan J, Wang F, Jiang Z, Lin G, Huang L, Pu X, Lin R, Liu W, Rao C, Lv D, Yu Z, Li X, Tang C, Zhou C, Zhang J, Xue J, Guo H, Chu Q, Meng R, Liu X, Wu J, Zhang R, Zhou J, Zhu Z, Li Y, Qiu H, Xia F, Lu Y, Chen X, Feng J, Ge R, Dai E, Han Y, Pan W, Pang F, Huang X, Hu M, Hao Q, Wang K, Wu F, Song B, Xu B, Wang L, Zhu Y, Lin L, Xie Y, Lin X, Cai J, Xu L, Li J, Jiao X, Li K, Wei J, Feng H, Wang L, Du Y, Yao W, Shi X, Niu X, Yuan D, Yao Y, Huang J, Feng Y, Zhang Y, Sun P, Wang H, Ye M, Wang D, Wang Z, Hao Y, Wang Z, Wan B, Lv D, Yang S, Kang J, Zhang J, Zhang C, Li W, Fu J, Wu L, Lan S, Ou J, Shi L, Zhai Z, Wang Y, Li B, Zhang Z, Wang K, Ma X, Li Z, Liu Z, Yang N, Wu L, Wang H, Jin G, Wang G, Wang J, Shi H, Fang M, Fang Y, Li Y, Wang X, Chen J, Zhang Y, Zhu X, Shen Y, Ma S, Wang B, Song Y, Song Z, Fang W, Lu Y, Si L. Expert consensus on the diagnosis and treatment of solid tumors with BRAF mutations. Innovation (N Y) 2024; 5:100661. [PMID: 39529955 PMCID: PMC11551471 DOI: 10.1016/j.xinn.2024.100661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/19/2024] [Indexed: 11/16/2024] Open
Abstract
The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth, differentiation, and survival. When the BRAF gene mutates, it can lead to abnormal activation of the signaling pathway, which promotes cell proliferation, inhibits cell apoptosis, and ultimately contributes to the occurrence and development of cancer. BRAF mutations are widely present in various cancers, including malignant melanoma, thyroid cancer, colorectal cancer, non-small cell lung cancer, and hairy cell leukemia, among others. BRAF is an important target for the treatment of various solid tumors, and targeted combination therapies, represented by BRAF inhibitors, have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors. Dabrafenib plus trametinib, as the first tumor-agnostic therapy, has been approved by the US Food and Drug Administration for the treatment of adult and pediatric patients aged 6 years and older harboring a BRAF V600E mutation with unresectable or metastatic solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. This is also the first time a BRAF/MEK inhibitor combination has been approved for use in pediatric patients. As research into the diagnosis and treatment of BRAF mutations advances, standardizing the detection of BRAF mutations and the clinical application of BRAF inhibitors becomes increasingly important. Therefore, we have established a universal and systematic strategy for diagnosing and treating solid tumors with BRAF mutations. In this expert consensus, we (1) summarize the epidemiology and clinical characteristics of BRAF mutations in different solid tumors, (2) provide recommendations for the selection of genetic testing methods and platforms, and (3) establish a universal strategy for the diagnosis and treatment of patients with solid tumors harboring BRAF mutations.
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Affiliation(s)
- Wenxian Wang
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Bin Lian
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Chunwei Xu
- Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Qian Wang
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Ziming Li
- Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Nan Zheng
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 200030, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 200030, China
| | - Aijun Liu
- Senior Department of Pathology, the 7 Medical Center of PLA General Hospital, Beijing 100700, P.R. China
| | - Jinpu Yu
- Department of Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Wenzhao Zhong
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou, Guangdong 510080, P.R. China
| | - Zhijie Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Yongchang Zhang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Jingjing Liu
- Department of Thoracic Cancer, Jilin Cancer Hospital, Jilin, Changchun 130012, P.R. China
| | - Shirong Zhang
- Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, West Lake University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiuyu Cai
- Department of VIP Inpatient, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. ChinaP.R. China
| | - Anwen Liu
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wen Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Lili Mao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Ping Zhan
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Hongbing Liu
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Tangfeng Lv
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Liyun Miao
- Department of Respiratory Medicine, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Lingfeng Min
- Department of Respiratory Medicine, Clinical Medical School of Yangzhou University, Subei People’s Hospital of Jiangsu Province, Yangzhou, Jiangsu 225001, P.R. China
| | - Yu Chen
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Jingping Yuan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Feng Wang
- Department of Internal Medicine, Cancer Center of PLA, Qinhuai Medical Area, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Zhansheng Jiang
- Derpartment of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Gen Lin
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Long Huang
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xingxiang Pu
- Department of Medical Oncology, Lung Cancer and Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Rongbo Lin
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Weifeng Liu
- Department of Orthopaedic Oncology Surgery, Beijing Ji Shui Tan Hospital, Peking University, Beijing 100035, P.R. China
| | - Chuangzhou Rao
- Department of Radiotherapy and Chemotherapy, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, P.R. China
| | - Dongqing Lv
- Department of Pulmonary Medicine, Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China
| | - Zongyang Yu
- Department of Respiratory Medicine, the 900 Hospital of the Joint Logistics Team (the Former Fuzhou General Hospital), Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Xiaoyan Li
- Department of Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100700, P.R. China
| | - Chuanhao Tang
- Department of Medical Oncology, Peking University International Hospital, Beijing 102206, P.R. China
| | - Chengzhi Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510300, P.R. China
| | - Junping Zhang
- Department of Thoracic Oncology, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200123, P.R. China
| | - Hui Guo
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Rui Meng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xuewen Liu
- Department of Oncology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Jingxun Wu
- Department of Medical Oncology, the First Affiliated Hospital of Medicine, Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Rui Zhang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
| | - Jin Zhou
- Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology, Chengdu, Sichuan 610041, P.R. China
| | - Zhengfei Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Yongheng Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Fan Xia
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Yuanyuan Lu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi 710032, P.R. China
| | - Xiaofeng Chen
- Department of Oncology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, Jiangsu 210029, P.R. China
| | - Jian Feng
- Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Rui Ge
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China
| | - Enyong Dai
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 13003, P.R. China
| | - Yu Han
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 1550081, P.R. China
| | - Weiwei Pan
- Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Fei Pang
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Xin Huang
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Meizhen Hu
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Qing Hao
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Kai Wang
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Fan Wu
- Department of Medical, Menarini Silicon Biosystems Spa, Shanghai 400000, P.R. China
| | - Binbin Song
- Department of Medical Oncology, The Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Bingwei Xu
- Department of Biotherapy, Cancer Institute, First Affiliated Hospital of China Medical University, Shenyang 110001, P.R. China
| | - Liping Wang
- Department of Oncology, Baotou Cancer Hospital, Baotou, Inner Mongolia 014000, P.R. China
| | - Youcai Zhu
- Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, The Third Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Li Lin
- Department of Medical Oncology, Peking University International Hospital, Beijing 102206, P.R. China
| | - Yanru Xie
- Department of Oncology, Lishui Municipal Central Hospital, Lishui, Zhejiang 323000, P.R. China
| | - Xinqing Lin
- Department of Radiotherapy and Chemotherapy, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, P.R. China
| | - Jing Cai
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ling Xu
- Department of Interventional Pulmonary Diseases, Anhui Chest Hospital, Hefei, Anhui 230011, P.R. China
| | - Jisheng Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinnan, Shangdong 250012, P.R. China
| | - Xiaodong Jiao
- Department of Medical Oncology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200070, P.R. China
| | - Kainan Li
- Department of Oncology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250031, P.R. China
| | - Jia Wei
- Department of the Comprehensive Cancer Center, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Huijing Feng
- Department of Thoracic Oncology, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Lin Wang
- Department of Pathology, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Yingying Du
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Wang Yao
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Xuefei Shi
- Department of Respiratory Medicine, Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang 313000, P.R. China
| | - Xiaomin Niu
- Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Dongmei Yuan
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Yanwen Yao
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jianhui Huang
- Department of Oncology, Lishui Municipal Central Hospital, Lishui, Zhejiang 323000, P.R. China
| | - Yue Feng
- Department of Gynecologic Radiation Oncology, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Yinbin Zhang
- Department of Oncology, the Second Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, Shaanxi 710004, P.R. China
| | - Pingli Sun
- Department of Pathology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Hong Wang
- Senior Department of Oncology, The 5 Medical Center of PLA General Hospital, Beijing 100071, P.R. China
| | - Mingxiang Ye
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Dong Wang
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Zhaofeng Wang
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Yue Hao
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Zhen Wang
- Department of Radiation Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Bin Wan
- Department of Respiratory Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Donglai Lv
- Department of Clinical Oncology, The 901 Hospital of Joint Logistics Support Force of People Liberation Army, Hefei, Anhui 230031, P.R. China
| | - Shengjie Yang
- Department of Thoracic Surgery, Chuxiong Yi Autonomous Prefecture People’s Hospital, Chuxiong, Yunnan 675000, P.R. China
| | - Jin Kang
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou, Guangdong 510080, P.R. China
| | - Jiatao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou, Guangdong 510080, P.R. China
| | - Chao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou, Guangdong 510080, P.R. China
| | - Wenfeng Li
- Department of Radiation Oncology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325000, China
| | - Jianfei Fu
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, P.R. China
| | - Lizhi Wu
- Department of Microsurgery, Taizhou Hospital Affiliated to Wenzhou Medical University, Taizhou, Zhejiang 317000, China
| | - Shijie Lan
- Department of Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Juanjuan Ou
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China
| | - Lin Shi
- Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhanqiang Zhai
- Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, The Third Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Yina Wang
- Department of Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Bihui Li
- Department of Oncology, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China
| | - Zhang Zhang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Ke Wang
- National Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 210000, People's Republic of China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zhongwu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Zhefeng Liu
- Senior Department of Oncology, The 5 Medical Center of PLA General Hospital, Beijing 100071, P.R. China
| | - Nong Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Lin Wu
- Department of Medical Oncology, Lung Cancer and Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Huijuan Wang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450000, P.R. China
| | - Gu Jin
- Department of Bone and Soft-tissue Surgery, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Guansong Wang
- Institute of Respiratory Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Jiandong Wang
- Department of Pathology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Hubing Shi
- Frontier Science Center for Disease Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Meiyu Fang
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Yong Fang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Yuan Li
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Xiaojia Wang
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Jing Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yiping Zhang
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Xixu Zhu
- Department of Radiation Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Yi Shen
- Department of Thoracic Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Shenglin Ma
- Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Biyun Wang
- Department of Breast Cancer and Urological Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Yong Song
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Zhengbo Song
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Wenfeng Fang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China
| | - Yuanzhi Lu
- Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Lu Si
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
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12
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Xiao A, Fakih M. KRAS G12C Inhibitors in the Treatment of Metastatic Colorectal Cancer. Clin Colorectal Cancer 2024; 23:199-206. [PMID: 38825433 DOI: 10.1016/j.clcc.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 05/11/2024] [Indexed: 06/04/2024]
Abstract
KRAS mutations contribute substantially to the overall colorectal cancer burden and have long been a focus of drug development efforts. After a lengthy preclinical road, KRAS inhibition via the G12C allele has finally become a therapeutic reality. Unlike in NSCLC, early studies of KRAS inhibitors in CRC struggled to demonstrate single agent activity. Investigation into these tissue-specific treatment differences has led to a deeper understanding of the complexities of MAPK signaling and the diverse adaptive feedback responses to KRAS inhibition. EGFR reactivation has emerged as a principal resistance mechanism to KRAS inhibitor monotherapy. Thus, the field has pivoted to dual EGFR/KRAS blockade with promising efficacy. Despite significant strides in the treatment of KRAS G12C mutated CRC, new challenges are on the horizon. Alternative RTK reactivation and countless acquired molecular resistance mechanisms have shifted the treatment goalpost. This review focuses on the historical and contemporary clinical strategies of targeting KRAS G12C alterations in CRC and highlights future directions to overcome treatment challenges.
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Affiliation(s)
- Annie Xiao
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd. Duarte, CA
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd. Duarte, CA.
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13
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Ueberroth BE, Lieu CH, Lentz RW. Prolonged Response to Dabrafenib/Trametinib in Grade 3 Metastatic Pancreatic Neuroendocrine Tumor (NET G3) with BRAF V600E Mutation. J Gastrointest Cancer 2024; 55:1448-1452. [PMID: 38814411 PMCID: PMC11347462 DOI: 10.1007/s12029-024-01072-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2024] [Indexed: 05/31/2024]
Abstract
PURPOSE Treatment of metastatic pancreatic neuroendocrine tumors (pancNETs), particularly grade 2 (G2) and grade 3 (G3), often presents a dilemma in choosing from multiple similarly efficacious therapies. Data on targeted therapies for these tumor types is limited, and this report presents BRAF-targeted therapy as a therapeutic option for metastatic pancNET G3. METHODS This is a case report of a patient with G3 pancNET metastatic to the liver, lung, lymph node, and scalp (soft tissue) treated with dabrafenib/trametinib (D/T) in the presence of a BRAF V600E mutation detected in tumor tissue. RESULTS This patient has demonstrated an ongoing partial response to therapy at all involved sites for nearly 15 months with minimal side effects attributable to D/T. CONCLUSION Dabrafenib/trametinib therapy for BRAF-mutated metastatic pancNETs provides a novel treatment option and, especially in the G3 setting, should be considered a first-line option. Tumor testing for actionable mutations should be undertaken at the time of diagnosis and/or progression to identify novel therapeutic avenues in these rare tumors.
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Affiliation(s)
- Benjamin E Ueberroth
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, 12801 E 17th Ave, MS 8117, Aurora, CO, 80045, USA.
| | - Christopher H Lieu
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, 12801 E 17th Ave, MS 8117, Aurora, CO, 80045, USA
| | - Robert W Lentz
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, 12801 E 17th Ave, MS 8117, Aurora, CO, 80045, USA
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14
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Piercey O, Tie J, Hollande F, Wong HL, Mariadason J, Desai J. BRAF V600E-Mutant Metastatic Colorectal Cancer: Current Evidence, Future Directions, and Research Priorities. Clin Colorectal Cancer 2024; 23:215-229. [PMID: 38816264 DOI: 10.1016/j.clcc.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 04/24/2024] [Indexed: 06/01/2024]
Abstract
BRAFV600E-mutant metastatic colorectal cancer represents a distinct molecular phenotype known for its aggressive biological behavior, resistance to standard therapies, and poor survival rates. Improved understanding of the biology of the BRAF oncogene has led to the development of targeted therapies that have paved the way for a paradigm shift in managing this disease. However, despite significant recent advancements, responses to targeted therapies are short-lived, and several challenges remain. In this review, we discuss how progress in treating BRAFV600E-mutant metastatic colorectal cancer has been made through a better understanding of its unique biological and clinical features. We provide an overview of the evidence to support current treatment approaches and discuss critical areas of need and future research strategies that hold the potential to refine clinical practice further. We also discuss some challenging aspects of managing this disease, particularly the complexity of acquired resistance mechanisms that develop under the selective pressure of targeted therapies and rational strategies being investigated to overcome them.
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Affiliation(s)
- Oliver Piercey
- Peter MacCallum Cancer Centre, Melbourne, Australia; Centre for Cancer Research, The University of Melbourne, Melbourne, Australia; Department of Clinical Pathology, The University of Melbourne, Australia.
| | - Jeanne Tie
- Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
| | - Frederic Hollande
- Centre for Cancer Research, The University of Melbourne, Melbourne, Australia; Department of Clinical Pathology, The University of Melbourne, Australia
| | - Hui-Li Wong
- Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
| | - John Mariadason
- Olivia Newton John Cancer Wellness and Research Centre, Heidelberg, Australia; School of Medicine, La Trobe University, Melbourne, Australia
| | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
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15
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Wang M, Sullivan RJ, Mooradian MJ. Toxicities from BRAF and MEK Inhibitors: Strategies to Maximize Therapeutic Success. Curr Oncol Rep 2024; 26:934-944. [PMID: 38850505 DOI: 10.1007/s11912-024-01544-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2024] [Indexed: 06/10/2024]
Abstract
PURPOSE OF REVIEW This report highlights several of the recent therapeutic advancements in the treatment of BRAF-mutant tumors, discusses the most common adverse events observed with BRAF-targeted agents, and suggests strategies to manage and mitigate treatment-related toxicities. RECENT FINDINGS BRAF and MEK inhibitors represent a significant advancement in the treatment of BRAF-mutated malignancies with data across tumor types demonstrating the anti-tumor efficacy of dual MAPK inhibition. Although these agents have a reasonable toxicity profile, variable side effects across organ systems can develop. The discovery of activating BRAF mutations and subsequent development of BRAF and MEK inhibitors has transformed the treatment algorithms of BRAF-mutant malignancies. With increased application of these targeted regimens, identification and prompt management of their unique adverse events are crucial.
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Affiliation(s)
- Mike Wang
- Division of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Ryan J Sullivan
- Division of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Meghan J Mooradian
- Division of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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16
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Owaki S, Mori Y, Nakai S, Maeda H, Imazu M, Tomita Y, Kanaiwa H, Yamaguchi A, Kitagawa M, Hirano A, Kimura Y, Tsuchida K, Kataoka H. BRAF V600E-mutated Colorectal Neuroendocrine Carcinoma Effectively Treated with a Chemotherapy Protocol for BRAF-mutated Metastatic Colorectal Cancer. Intern Med 2024; 63:1995-1999. [PMID: 37981300 PMCID: PMC11309870 DOI: 10.2169/internalmedicine.2870-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 10/05/2023] [Indexed: 11/21/2023] Open
Abstract
Metastatic colorectal neuroendocrine carcinoma (NEC) is often treated using a chemotherapy protocol for small-cell lung cancer; however, the prognosis is extremely poor. A 55-year-old woman with BRAF V600E-mutated transverse colon NEC and liver metastases underwent colectomy followed by FOLFOXIRI plus bevacizumab. Consequently, the liver metastases markedly shrank. Owing to later worsening of the liver metastases, she received encorafenib and binimetinib plus cetuximab. Despite discontinuing binimetinib due to myalgia, she had a long-term response with a progression-free survival of 14 months and an overall survival of more than 27 months. A chemotherapy protocol for BRAF-mutated metastatic colorectal cancer may be a treatment option for BRAF V600E-mutated colorectal NEC.
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Affiliation(s)
- Seira Owaki
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
- Department of Medical Oncology, National Hospital Organization Nagoya Medical Center, Japan
| | - Yoshinori Mori
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Shunsuke Nakai
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Hideki Maeda
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Mitsuki Imazu
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Yusaku Tomita
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Hiroki Kanaiwa
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Ayana Yamaguchi
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Mika Kitagawa
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Atsuyuki Hirano
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Yoshihide Kimura
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Kenji Tsuchida
- Department of Gastroenterology, Nagoya City University West Medical Center, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan
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17
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Thein KZ, Myat YM, Park BS, Panigrahi K, Kummar S. Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development. Cancers (Basel) 2024; 16:2529. [PMID: 39061168 PMCID: PMC11274498 DOI: 10.3390/cancers16142529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 07/06/2024] [Indexed: 07/28/2024] Open
Abstract
The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.
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Affiliation(s)
- Kyaw Z. Thein
- Division of Hematology and Medical Oncology, Comprehensive Cancer Centers of Nevada—Central Valley, 3730 S Eastern Ave, Las Vegas, NV 89169, USA
- Department of Medicine, Kirk Kerkorian School of Medicine, University of Nevada Las Vegas (UNLV), 4505 S, Maryland Pkwy, Las Vegas, NV 89154, USA
- College of Osteopathic Medicine, Touro University Nevada, Touro College and University System, 874 American Pacific Dr, Henderson, NV 89014, USA
| | - Yin M. Myat
- Belfield Campus, University College Dublin (UCD) School of Medicine, D04 V1W8 Dublin, Ireland;
- Department of Internal Medicine, One Brooklyn Health—Interfaith Medical Center Campus, 1545, Atlantic Avenue, Brooklyn, NY 11213, USA;
| | - Byung S. Park
- OHSU-PSU School of Public Health, Portland, OR 97201, USA;
- Biostatistics Shared Resource, OHSU Knight Cancer Institute, OHSU School of Medicine, Portland, OR 97239, USA
| | - Kalpana Panigrahi
- Department of Internal Medicine, One Brooklyn Health—Interfaith Medical Center Campus, 1545, Atlantic Avenue, Brooklyn, NY 11213, USA;
| | - Shivaani Kummar
- Division of Hematology & Medical Oncology, Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA;
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18
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Singh M, Morris VK, Bandey IN, Hong DS, Kopetz S. Advancements in combining targeted therapy and immunotherapy for colorectal cancer. Trends Cancer 2024; 10:598-609. [PMID: 38821852 DOI: 10.1016/j.trecan.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/01/2024] [Accepted: 05/03/2024] [Indexed: 06/02/2024]
Abstract
Colorectal cancer (CRC) is a prevalent gastrointestinal cancer posing significant clinical challenges. CRC management traditionally involves surgery, often coupled with chemotherapy. However, unresectable or metastatic CRC (mCRC) presents a complex challenge necessitating innovative treatment strategies. Targeted therapies have emerged as the cornerstone of treatment in such cases, with interventions tailored to specific molecular attributes. Concurrently, immunotherapies have revolutionized cancer treatment by harnessing the immune system to combat malignant cells. This review explores the evolving landscape of CRC treatment, focusing on the synergy between immunotherapies and targeted therapies, thereby offering new avenues for enhancing the effectiveness of therapy for CRC.
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Affiliation(s)
- Manisha Singh
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Van Karlyle Morris
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Irfan N Bandey
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David S Hong
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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19
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Napolitano S, Martini G, Ciardiello D, Del Tufo S, Martinelli E, Troiani T, Ciardiello F. Targeting the EGFR signalling pathway in metastatic colorectal cancer. Lancet Gastroenterol Hepatol 2024; 9:664-676. [PMID: 38697174 DOI: 10.1016/s2468-1253(23)00479-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 12/21/2023] [Accepted: 12/28/2023] [Indexed: 05/04/2024]
Abstract
Epidermal growth factor receptor (EGFR) and its activated downstream signalling pathways play a crucial role in colorectal cancer development and progression. After four decades of preclinical, translational, and clinical research, it has been shown that blocking the EGFR signalling pathway at different molecular levels represents a fundamental therapeutic strategy for patients with metastatic colorectal cancer. Nevertheless, the efficacy of molecularly targeted therapies is inescapably limited by the insurgence of mechanisms of acquired cancer cell resistance. Thus, in the era of precision medicine, a deeper understanding of the complex molecular landscape of metastatic colorectal cancer is required to deliver the best treatment choices to all patients. Major efforts are currently ongoing to improve patient selection, improve the efficacy of available treatments targeting the EGFR pathway, and develop novel combination strategies to overcome therapy resistance within the continuum of care of metastatic colorectal cancer.
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Affiliation(s)
- Stefania Napolitano
- Department of Precision Medicine, Università degli studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Giulia Martini
- Department of Precision Medicine, Università degli studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Davide Ciardiello
- Department of Precision Medicine, Università degli studi della Campania Luigi Vanvitelli, Napoli, Italy; Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Sara Del Tufo
- Department of Precision Medicine, Università degli studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Erika Martinelli
- Department of Precision Medicine, Università degli studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Teresa Troiani
- Department of Precision Medicine, Università degli studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Fortunato Ciardiello
- Department of Precision Medicine, Università degli studi della Campania Luigi Vanvitelli, Napoli, Italy.
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20
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Chen Y, Sang Y, Li S, Xue J, Chen M, Hong S, Lv W, Sehgal K, Xiao H, Liu R. The ERK inhibitor GDC-0994 selectively inhibits growth of BRAF mutant cancer cells. Transl Oncol 2024; 45:101991. [PMID: 38728872 PMCID: PMC11107342 DOI: 10.1016/j.tranon.2024.101991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/23/2024] [Accepted: 05/06/2024] [Indexed: 05/12/2024] Open
Abstract
BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. The results showed that GDC-0994 sharply inhibited cell proliferation and colony formation and induced remarkable G1 phase cell-cycle arrest in cancer cells harboring BRAF mutation but had little effect on cell behaviors in most RAS mutant or wild-type cell lines. The expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells. Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.
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Affiliation(s)
- Yulu Chen
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong 510080, China
| | - Ye Sang
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong 510080, China
| | - Shiyong Li
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong 510080, China
| | - Junyu Xue
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong 510080, China
| | - Mengke Chen
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong 510080, China
| | - Shubin Hong
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong 510080, China
| | - Weiming Lv
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Kartik Sehgal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Haipeng Xiao
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong 510080, China.
| | - Rengyun Liu
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong 510080, China.
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21
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Gu R, Fang H, Wang R, Dai W, Cai G. A comprehensive overview of the molecular features and therapeutic targets in BRAF V600E-mutant colorectal cancer. Clin Transl Med 2024; 14:e1764. [PMID: 39073010 PMCID: PMC11283586 DOI: 10.1002/ctm2.1764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/23/2024] [Accepted: 07/03/2024] [Indexed: 07/30/2024] Open
Abstract
As one of the most prevalent digestive system tumours, colorectal cancer (CRC) poses a significant threat to global human health. With the emergence of immunotherapy and target therapy, the prognosis for the majority of CRC patients has notably improved. However, the subset of patients with BRAF exon 15 p.V600E mutation (BRAFV600E) has not experienced remarkable benefits from these therapeutic advancements. Hence, researchers have undertaken foundational investigations into the molecular pathology of this specific subtype and clinical effectiveness of diverse therapeutic drug combinations. This review comprehensively summarised the distinctive molecular features and recent clinical research advancements in BRAF-mutant CRC. To explore potential therapeutic targets, this article conducted a systematic review of ongoing clinical trials involving patients with BRAFV600E-mutant CRC.
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Affiliation(s)
- Ruiqi Gu
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Hongsheng Fang
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Renjie Wang
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Weixing Dai
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Guoxiang Cai
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
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22
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Salva de Torres C, Baraibar I, Saoudi González N, Ros J, Salva F, Rodríguez-Castells M, Alcaraz A, García A, Tabernero J, Élez E. Current and Emerging Treatment Paradigms in Colorectal Cancer: Integrating Hallmarks of Cancer. Int J Mol Sci 2024; 25:6967. [PMID: 39000083 PMCID: PMC11241496 DOI: 10.3390/ijms25136967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. 'The Hallmarks of Cancer' illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients' outcomes.
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Affiliation(s)
| | - Iosune Baraibar
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Nadia Saoudi González
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Javier Ros
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Francesc Salva
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Marta Rodríguez-Castells
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Adriana Alcaraz
- Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (A.A.); (A.G.)
| | - Ariadna García
- Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (A.A.); (A.G.)
| | - Josep Tabernero
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
| | - Elena Élez
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), E-08035 Barcelona, Spain; (I.B.); (N.S.G.); (J.R.); (F.S.); (M.R.-C.), (J.T.)
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23
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Harrold E, Keane F, Walch H, Chou JF, Sinopoli J, Palladino S, Al-Rawi DH, Chadalavada K, Manca P, Chalasani S, Yang J, Cercek A, Shia J, Capanu M, Bakhoum SF, Schultz N, Chatila WK, Yaeger R. Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer. Clin Cancer Res 2024; 30:2672-2683. [PMID: 38502113 PMCID: PMC11176917 DOI: 10.1158/1078-0432.ccr-23-4005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 02/19/2024] [Accepted: 03/15/2024] [Indexed: 03/20/2024]
Abstract
PURPOSE Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance. EXPERIMENTAL DESIGN We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT). RESULTS All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases. CONCLUSIONS Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.
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Affiliation(s)
- Emily Harrold
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Fergus Keane
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Henry Walch
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joanne F. Chou
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jenna Sinopoli
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Silvia Palladino
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Duaa H. Al-Rawi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kalyani Chadalavada
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Paolo Manca
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sree Chalasani
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Jessica Yang
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marinela Capanu
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Samuel F. Bakhoum
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nikolaus Schultz
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Walid K. Chatila
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
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24
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Shi Y, Han X, Zhao Q, Zheng Y, Chen J, Yu X, Fang J, Liu Y, Huang D, Liu T, Shen H, Luo S, Yu H, Cao Y, Zhang X, Hu P. Tunlametinib (HL-085) plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors: an open-label, single-arm, multicenter, phase I study. Exp Hematol Oncol 2024; 13:60. [PMID: 38867257 PMCID: PMC11167782 DOI: 10.1186/s40164-024-00528-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 06/03/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Tunlametinib (HL-085) is a novel, highly selective MEK inhibitor with substantial clinical activities in patients with NRAS-mutant melanoma. This phase I study evaluated the safety and preliminary efficacy of tunlametinib plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors. METHODS Patients with confirmed advanced BRAF V600-mutant solid tumors who had progressed on or shown intolerance or no available standard therapies were enrolled and received tunlametinib plus vemurafenib. This study consisted of a dose-escalation phase and a dose-expansion phase. Primary end points of this study were safety, the recommended phase II dose (RP2D), and preliminary efficacy. RESULTS From August 17, 2018 to April 19, 2022, 72 patients were enrolled. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. The RP2D for BRAF V600-mutant non-small cell lung cancer (NSCLC) patients was tunlametinib 9 mg plus vemurafenib 720 mg, twice daily (BID, bis in die). Until the data cut-off date of December 15, 2023, of 33 NSCLC patients with evaluable disease, the objective response rate (ORR) was 60.6% (20/33; 95% confidence interval [CI], 42.1-77.1), the median progression free survival (PFS) was 10.5 months (95%CI, 5.6-14.5) and median duration of response (DoR) was 11.3 months (95%CI, 6.8-NE). At the RP2D, ORR was 60.0% (9/15; 95% CI, 32.3-83.7), the median PFS was 10.5 months (95%CI, 5.6 -NE) and median DoR was 11.3 months (95%CI, 3.9-NE). Of 24 colorectal cancer patients with evaluable disease, the ORR was 25.0% (6/24; 95% CI, 5.6-NE). All 72 patients had treatment-related adverse events (TRAEs), and the most common grade 3-4 TRAEs were anemia (n = 13, 18.1%) and blood creatine phosphokinase increased (n = 10, 13.9%). Tunlametinib was absorbed rapidly with Tmax of 0.5-1 h. Vemurafeinib did not influence the system exposure of tunlametinib and vice versa, indicating no drug-drug interaction for this combination. CONCLUSIONS Tunlametinib (HL-085) plus vemurafenib had a favorable safety profile and showed promising antitumor activity in patients with BRAF V600-mutant solid tumors. The RP2D for NSCLC was tunlametinib 9 mg BID plus vemurafeinib 720 mg BID. TRIAL REGISTRATION ClinicalTrials.gov, NCT03781219.
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Affiliation(s)
- Yuankai Shi
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.
| | - Xiaohong Han
- Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1, Shuaifuyuan, Dongcheng District, Beijing, 100730, People's Republic of China
| | - Qian Zhao
- Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1, Shuaifuyuan, Dongcheng District, Beijing, 100730, People's Republic of China
| | - YuLong Zheng
- Department of Oncology, the First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, 310006, People's Republic of China
| | - Jianhua Chen
- Thoracic Medicine Department I, the Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan Province, 410006, People's Republic of China
| | - Xinmin Yu
- Department of Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang Province, 310022, People's Republic of China
| | - Jian Fang
- Thoracic Oncology Second Department, Beijing Cancer Hospital, Beijing, 100142, People's Republic of China
| | - Yutao Liu
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China
| | - Dingzhi Huang
- Department of Thoracic Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Hong Shen
- Department of Oncology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310009, People's Republic of China
| | - Suxia Luo
- Department of Medical Oncology, Henan Cancer Hospital, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450008, People's Republic of China
| | - Hongsheng Yu
- Department of Radiation Oncology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266000, People's Republic of China
| | - Yu Cao
- Phase I Clinical Research Center, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266000, People's Republic of China
| | - Xi Zhang
- Department of Clinical Research and Development, Shanghai Kechow Pharma, Inc, Shanghai, 201203, People's Republic of China
| | - Pei Hu
- Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1, Shuaifuyuan, Dongcheng District, Beijing, 100730, People's Republic of China
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25
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Beech C, Hechtman JF. Molecular Approach to Colorectal Carcinoma: Current Evidence and Clinical Application. Clin Lab Med 2024; 44:221-238. [PMID: 38821642 DOI: 10.1016/j.cll.2023.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2024]
Abstract
Colorectal carcinoma is one of the most common cancer types in men and women, responsible for both the third highest incidence of new cancer cases and the third highest cause of cancer deaths. In the last several decades, the molecular mechanisms surrounding colorectal carcinoma's tumorigenesis have become clearer through research, providing new avenues for diagnostic testing and novel approaches to therapeutics. Laboratories are tasked with providing the most current information to help guide clinical decisions. In this review, we summarize the current knowledge surrounding colorectal carcinoma tumorigenesis and highlight clinically relevant molecular testing.
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Affiliation(s)
- Cameron Beech
- Department of Pathology, Yale New Haven Hospital, New Haven, CT, USA
| | - Jaclyn F Hechtman
- Molecular and GI Pathologist, NeoGenomics Laboratories, Fort Myers, FL, USA.
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26
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Peralta S, Katt W, Balkman C, Butler S, Carney P, Todd-Donato A, Drozd M, Duhamel G, Fiani N, Ford J, Grenier J, Hayward J, Heikinheimo K, Hume K, Moore E, Puri R, Sylvester S, Warshaw S, Webb S, White A, Wright A, Cerione R. Opportunities for targeted therapies: trametinib as a therapeutic approach to canine oral squamous cell carcinomas. RESEARCH SQUARE 2024:rs.3.rs-4289451. [PMID: 38746473 PMCID: PMC11092801 DOI: 10.21203/rs.3.rs-4289451/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. OSCCs have significant upregulation of the RAS-RAF-MEK-MAPK signaling axis, and we had previously hypothesized that small-molecule inhibitors that target RAS signaling might effectively inhibit tumor growth and progression. Here, we demonstrate that the MEK inhibitor trametinib, an FDA-approved drug for human cancers, significantly blocks the growth of several COSCC cell lines established from current patient tumor samples. We further show clinical evidence that the drug is able to cause significant tumor regression in some patients with spontaneously occurring COSCC. Given the limited treatment options available and the high rate of owner rejection of these offered options, these findings provide new hope that more acceptable treatment options may soon enter the veterinary clinic.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Jennifer Grenier
- RNA Sequencing Core and Center for Reproductive Genomics. Cornell University, Ithaca, NY
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27
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Perurena N, Situ L, Cichowski K. Combinatorial strategies to target RAS-driven cancers. Nat Rev Cancer 2024; 24:316-337. [PMID: 38627557 DOI: 10.1038/s41568-024-00679-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/22/2024] [Indexed: 05/01/2024]
Abstract
Although RAS was formerly considered undruggable, various agents that inhibit RAS or specific RAS oncoproteins have now been developed. Indeed, the importance of directly targeting RAS has recently been illustrated by the clinical success of mutant-selective KRAS inhibitors. Nevertheless, responses to these agents are typically incomplete and restricted to a subset of patients, highlighting the need to develop more effective treatments, which will likely require a combinatorial approach. Vertical strategies that target multiple nodes within the RAS pathway to achieve deeper suppression are being investigated and have precedence in other contexts. However, alternative strategies that co-target RAS and other therapeutic vulnerabilities have been identified, which may mitigate the requirement for profound pathway suppression. Regardless, the efficacy of any given approach will likely be dictated by genetic, epigenetic and tumour-specific variables. Here we discuss various combinatorial strategies to treat KRAS-driven cancers, highlighting mechanistic concepts that may extend to tumours harbouring other RAS mutations. Although many promising combinations have been identified, clinical responses will ultimately depend on whether a therapeutic window can be achieved and our ability to prospectively select responsive patients. Therefore, we must continue to develop and understand biologically diverse strategies to maximize our likelihood of success.
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Affiliation(s)
- Naiara Perurena
- Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Lisa Situ
- Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Karen Cichowski
- Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Ludwig Center, Harvard Medical School, Boston, MA, USA.
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28
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Corcoran RB, Do KT, Kim JE, Cleary JM, Parikh AR, Yeku OO, Xiong N, Weekes CD, Veneris J, Ahronian LG, Mauri G, Tian J, Norden BL, Michel AG, Van Seventer EE, Siravegna G, Camphausen K, Chi G, Fetter IJ, Brugge JS, Chen H, Takebe N, Penson RT, Juric D, Flaherty KT, Sullivan RJ, Clark JW, Heist RS, Matulonis UA, Liu JF, Shapiro GI. Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors. Clin Cancer Res 2024; 30:1739-1749. [PMID: 38456660 PMCID: PMC11061595 DOI: 10.1158/1078-0432.ccr-23-3135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/11/2023] [Accepted: 02/26/2024] [Indexed: 03/09/2024]
Abstract
PURPOSE MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.
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Affiliation(s)
- Ryan B. Corcoran
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Khanh T. Do
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jeong E. Kim
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - James M. Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Aparna R. Parikh
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Oladapo O. Yeku
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Niya Xiong
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Colin D. Weekes
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Jennifer Veneris
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Leanne G. Ahronian
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Gianluca Mauri
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, and Department of Hematology Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Jun Tian
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Bryanna L. Norden
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Alexa G. Michel
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Emily E. Van Seventer
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Giulia Siravegna
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Kyle Camphausen
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Gary Chi
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Isobel J. Fetter
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Joan S. Brugge
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
| | - Helen Chen
- National Institute of Health, National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Bethesda, Maryland
| | - Naoko Takebe
- National Institute of Health, National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Bethesda, Maryland
| | - Richard T. Penson
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Dejan Juric
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Keith T. Flaherty
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Ryan J. Sullivan
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Jeffrey W. Clark
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Rebecca S. Heist
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Ursula A. Matulonis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Joyce F. Liu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Geoffrey I. Shapiro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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Falkman L, Sundin A, Skogseid B, Botling J, Bernardo Y, Wallin G, Zhang L, Welin S, Lase I, Mollazadegan K, Crona J. Genetics-guided therapy in neuroendocrine carcinoma: response to BRAF- and MEK-inhibitors. Ups J Med Sci 2024; 129:10660. [PMID: 38716076 PMCID: PMC11075439 DOI: 10.48101/ujms.v129.10660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 06/04/2024] Open
Abstract
Background Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current guidelines suggest that combination treatment with BRAF-inhibitors should be considered for patients with BRAF V600E-mutated NEC. However, since only eight such patients have been reported in the literature, our object was to confirm the validity of this recommendation. Methods This was a single-center retrospective cohort study conducted at Uppsala University Hospital. The included patients 1) had a histopathologically confirmed diagnosis of NEC, 2) were diagnosed between January 1st, 2018 and December 31st, 2023, 3) had tumor tissue genetically screened by a broad next-generation sequencing (NGS) panel, and 4) showed a tumor mutation for which there is a currently available targeted therapy. Results We screened 48 patients diagnosed with NEC between January 1st, 2018 and December 31st, 2023. Twelve had been analyzed with a broad NGS-panel, and two had a targetable mutation. Both these patients harbored a BRAF V600E-mutated colon-NEC and were treated with BRAF- and MEK-inhibitors dabrafenib and trametinib in second-line. At first radiological evaluation (RECIST 1.1), both patients had a reduction of tumor size, which decreased by 31 and 40%. Both had short response periods, and their overall survival was 12 and 9 months. Conclusions BRAF-mutated NEC is sensitive to treatment with BRAF- and MEK-inhibitor combination. These results further support that DNA sequencing should be considered as standard of care in NECs to screen for potential treatment targets.
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Affiliation(s)
- Lovisa Falkman
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Anders Sundin
- Department of Radiology, Uppsala University Hospital, Uppsala, Sweden
| | - Britt Skogseid
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Johan Botling
- Institute of Biomedicine, Department of Laboratory Medicine, Gothenburg University, Gothenburg, Sweden
| | - Yvette Bernardo
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Göran Wallin
- Department of Surgery, Örebro University Hospital, Örebro, Sweden
| | - Liang Zhang
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Staffan Welin
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Ieva Lase
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Joakim Crona
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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30
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Aleksakhina SN, Ivantsov AO, Imyanitov EN. Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution. Int J Mol Sci 2024; 25:4094. [PMID: 38612902 PMCID: PMC11012409 DOI: 10.3390/ijms25074094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 03/27/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.
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Affiliation(s)
- Svetlana N. Aleksakhina
- Department of Tumor Growth Biology, N. N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia
| | - Alexander O. Ivantsov
- Department of Tumor Growth Biology, N. N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia
- Department of Medical Genetics, St. Petersburg Pediatric Medical University, 194100 St. Petersburg, Russia
| | - Evgeny N. Imyanitov
- Department of Tumor Growth Biology, N. N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia
- Department of Medical Genetics, St. Petersburg Pediatric Medical University, 194100 St. Petersburg, Russia
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Xiong F, Zhou YW, Hao YT, Wei GX, Chen XR, Qiu M. Combining Anti-epidermal Growth Factor Receptor (EGFR) Therapy with Immunotherapy in Metastatic Colorectal Cancer (mCRC). Expert Rev Gastroenterol Hepatol 2024; 18:185-192. [PMID: 37705376 DOI: 10.1080/17474124.2023.2232718] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/30/2023] [Indexed: 09/15/2023]
Abstract
INTRODUCTION Monoclonal antibodies binding the EGFR, such as cetuximab and panitumumab, have been extensively used as targeted therapy for the treatment of mCRC. However, in clinical practice, it has been found that these treatment options have some limitations and fail to fully exploit their immunoregulatory activities. Meanwhile, because of the limited effects of current treatments, immunotherapy is being widely studied for patients with mCRC. However, previous immunotherapy trials in mCRC patients have had unsatisfactory outcomes as monotherapy. Thus, combinatorial treatment strategies are being researched. AREAS COVERED The authors retrieved relevant documents of combination therapy for mCRC from PubMed and Medline. This review elaborates on the knowledge of immunomodulatory effects of anti-EGFR therapy alone and in combination with immunotherapy for mCRC. EXPERT OPINION Although current treatment options have improved median overall survival (OS) for advanced disease to 30 months, the prognosis remains challenging for those with metastatic disease. More recently, the combination of anti-EGFR therapy with immunotherapy has been shown activity with complementary mechanisms. Hence, anti-EGFR therapy in combination with immunotherapy may hold the key to improving the therapeutic effect of refractory mCRC.
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Affiliation(s)
- Feng Xiong
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yu-Wen Zhou
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Ya-Ting Hao
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Gui-Xia Wei
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xiao-Rong Chen
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
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Gmeiner WH. Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment. Cancers (Basel) 2024; 16:1029. [PMID: 38473386 PMCID: PMC10930828 DOI: 10.3390/cancers16051029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/24/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology.
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Affiliation(s)
- William H Gmeiner
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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Hanrahan AJ, Chen Z, Rosen N, Solit DB. BRAF - a tumour-agnostic drug target with lineage-specific dependencies. Nat Rev Clin Oncol 2024; 21:224-247. [PMID: 38278874 PMCID: PMC11857949 DOI: 10.1038/s41571-023-00852-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2023] [Indexed: 01/28/2024]
Abstract
In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAFV600E-mutant solid tumours, except for BRAFV600E-mutant colorectal cancers. The histology-agnostic approval of dabrafenib plus trametinib marks the culmination of two decades of research into the landscape of BRAF mutations in human cancers, the biochemical mechanisms underlying BRAF-mediated tumorigenesis, and the clinical development of selective RAF and MEK inhibitors. Although the majority of patients with BRAFV600E-mutant tumours derive clinical benefit from BRAF inhibitor-based combinations, resistance to treatment develops in most. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies.
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Affiliation(s)
- Aphrothiti J Hanrahan
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ziyu Chen
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Physiology, Biophysics & Systems Biology, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA
| | - Neal Rosen
- Molecular Pharmacology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - David B Solit
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Cornell Medical College, Cornell University, New York, NY, USA.
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Li B, Ming H, Qin S, Zhou L, Huang Z, Jin P, Peng L, Luo M, Zhang T, Wang K, Liu R, Liou Y, Nice EC, Jiang J, Huang C. HSPA8 Activates Wnt/β-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306535. [PMID: 37973552 PMCID: PMC10797426 DOI: 10.1002/advs.202306535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Indexed: 11/19/2023]
Abstract
BRAF V600E attracts wide attention in the treatment of colorectal cancer (CRC) as stratifying and predicting a refractory classification of CRC. Recent evidence indicates that Wnt/β-catenin signaling is broadly activated and participates in the refractoriness of BRAF V600E CRC, but the underlying molecular mechanism needs to be elucidated. Here, heat shock 70 kDa protein 8 (HSPA8), an essential regulator in chaperone-mediated autophagy (CMA), is identified as a potential therapeutic target for advanced BRAF V600E CRC. These results show that HSPA8 is transcriptionally upregulated in BRAF V600E CRC, which promotes CMA-dependent degradation of caveolin-1 (CAV1) to release β-catenin into the nucleus and thus activates the Wnt/β-catenin pathway, contributing to metastasis and progression of BRAF V600E CRC. Of note, HSPA8 directly interacts with the KIFSN motif on CAV1, the interaction can be enhanced by p38 MAPK-mediated CAV1 S168 phosphorylation. Furthermore, pharmacological targeting HSPA8 by VER155008 exhibits synergistic effects with BRAF inhibitors on CRC mouse models. In summary, these findings discover the important role of the HSPA8/CAV1/β-catenin axis in the development of refractory BRAF V600E CRC and highlight HSPA8 as a predictive biomarker and therapeutic target in clinical practice.
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Affiliation(s)
- Bowen Li
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Hui Ming
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Siyuan Qin
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Ping Jin
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Liyuan Peng
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Maochao Luo
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Tingting Zhang
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Kui Wang
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
| | - Rui Liu
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesChinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and ManagementWest China Hospital of StomatologySichuan UniversityChengduSichuan610041P. R. China
| | - Yih‐Cherng Liou
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingapore117543Singapore
- Graduate School for Integrative Sciences and EngineeringNational University of SingaporeSingapore117573Singapore
| | - Edouard C. Nice
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVIC3800Australia
| | - Jingwen Jiang
- West China School of Public Health and West China Fourth HospitalSichuan UniversityChengdu610041P. R. China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital and West China School of Basic Medical Sciences and Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengdu610041P. R. China
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Aiman W, Ali MA, Jumean S, Asfeen U, Garcia J, Quirem M, Ahmad A, Rayad MN, Alkhlaifat O, Al Omour B, Chemarthi VS, Maroules M, Guron G, Shaaban H. BRAF Inhibitors in BRAF-Mutated Colorectal Cancer: A Systematic Review. J Clin Med 2023; 13:113. [PMID: 38202120 PMCID: PMC10779564 DOI: 10.3390/jcm13010113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/17/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths globally. BRAF mutation is present in about 10% of CRC patients and is associated with a poor response to chemotherapy. These patients have a relatively poor prognosis. This review aims to assess the efficacy and safety of BRAF inhibitors in BRAF-mutated CRC patients. A literature search was performed on PubMed and Embase, and clinical trials relevant to BRAF inhibitors in CRC were included. Data were extracted for efficacy and safety variables. Two randomized clinical trials (n = 765) and eight non-randomized trials (n = 281) were included based on inclusion criteria. In RCTs, an overall response was reported in 23% of the patients treated with BRAF inhibitor-based regimens compared to 2.5% with control regimens. The hazard ratio of overall survival was also significantly better with triplet encorafenib therapy at 0.52 (95% CI = 0.39-0.70). In single-arm trials, ORR was 17% and 34% in two-drug and three-drug regimens, respectively. BRAF inhibitor-based regimens were safe and effective in the treatment of BRAF-mutated CRC. Large-scale randomized trials are needed to find a suitable population for each regimen. PROSPERO registration No. CRD42023471627.
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Affiliation(s)
- Wajeeha Aiman
- Department of Internal Medicine, Saint Michael’s Medical Center, New York Medical College, Newark, NJ 07102, USA; (W.A.); (S.J.); (U.A.); (J.G.); (M.Q.); (A.A.); (M.N.R.); (O.A.)
| | - Muhammad Ashar Ali
- Department of Internal Medicine, St. Mary’s and St. Clare’s Hospitals, New York Medical College, Denville, NJ 07834, USA
| | - Samer Jumean
- Department of Internal Medicine, Saint Michael’s Medical Center, New York Medical College, Newark, NJ 07102, USA; (W.A.); (S.J.); (U.A.); (J.G.); (M.Q.); (A.A.); (M.N.R.); (O.A.)
| | - Ummul Asfeen
- Department of Internal Medicine, Saint Michael’s Medical Center, New York Medical College, Newark, NJ 07102, USA; (W.A.); (S.J.); (U.A.); (J.G.); (M.Q.); (A.A.); (M.N.R.); (O.A.)
| | - Jose Garcia
- Department of Internal Medicine, Saint Michael’s Medical Center, New York Medical College, Newark, NJ 07102, USA; (W.A.); (S.J.); (U.A.); (J.G.); (M.Q.); (A.A.); (M.N.R.); (O.A.)
| | - Murad Quirem
- Department of Internal Medicine, Saint Michael’s Medical Center, New York Medical College, Newark, NJ 07102, USA; (W.A.); (S.J.); (U.A.); (J.G.); (M.Q.); (A.A.); (M.N.R.); (O.A.)
| | - Amaar Ahmad
- Department of Internal Medicine, Saint Michael’s Medical Center, New York Medical College, Newark, NJ 07102, USA; (W.A.); (S.J.); (U.A.); (J.G.); (M.Q.); (A.A.); (M.N.R.); (O.A.)
| | - Mohammad Nabil Rayad
- Department of Internal Medicine, Saint Michael’s Medical Center, New York Medical College, Newark, NJ 07102, USA; (W.A.); (S.J.); (U.A.); (J.G.); (M.Q.); (A.A.); (M.N.R.); (O.A.)
| | - Osama Alkhlaifat
- Department of Internal Medicine, Saint Michael’s Medical Center, New York Medical College, Newark, NJ 07102, USA; (W.A.); (S.J.); (U.A.); (J.G.); (M.Q.); (A.A.); (M.N.R.); (O.A.)
| | - Bader Al Omour
- Department of Hematology/Oncology, Saint Michael’s Cancer Center, New York Medical College, Newark, NJ 07102, USA (V.S.C.); (G.G.); (H.S.)
| | - Venkata S. Chemarthi
- Department of Hematology/Oncology, Saint Michael’s Cancer Center, New York Medical College, Newark, NJ 07102, USA (V.S.C.); (G.G.); (H.S.)
| | - Michael Maroules
- Department of Hematology/Oncology, Saint Mary’s Cancer Center, New York Medical College, Passaic, NJ 07055, USA;
| | - Gunwant Guron
- Department of Hematology/Oncology, Saint Michael’s Cancer Center, New York Medical College, Newark, NJ 07102, USA (V.S.C.); (G.G.); (H.S.)
| | - Hamid Shaaban
- Department of Hematology/Oncology, Saint Michael’s Cancer Center, New York Medical College, Newark, NJ 07102, USA (V.S.C.); (G.G.); (H.S.)
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Chapdelaine AG, Ku GC, Sun G, Ayrapetov MK. The Targeted Degradation of BRAF V600E Reveals the Mechanisms of Resistance to BRAF-Targeted Treatments in Colorectal Cancer Cells. Cancers (Basel) 2023; 15:5805. [PMID: 38136350 PMCID: PMC10741866 DOI: 10.3390/cancers15245805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/08/2023] [Accepted: 12/09/2023] [Indexed: 12/24/2023] Open
Abstract
The BRAF V600E mutation is frequently found in cancer. It activates the MAPK pathway and promotes cancer cell proliferation, making BRAF an excellent target for anti-cancer therapy. While BRAF-targeted therapy is highly effective for melanoma, it is often ineffective against other cancers harboring the BRAF mutation. In this study, we evaluate the effectiveness of a proteolysis targeting chimera (PROTAC), SJF-0628, in directing the degradation of mutated BRAF across a diverse panel of cancer cells and determine how these cells respond to the degradation. SJF-0628 treatment results in the degradation of BRAF V600E and a decrease in Mek activation in all cell lines tested, but the effects of the treatment on cell signaling and cell proliferation are cell-line-specific. First, BRAF degradation killed DU-4475 and Colo-205 cells via apoptosis but only partially inhibited the proliferation of other cancer cell lines. Second, SJF-0628 treatment resulted in co-degradation of MEK in Colo-205 cells but did not have the same effect in other cell lines. Finally, cell lines partially inhibited by BRAF degradation also contain other oncogenic drivers, making them multi-driver cancer cells. These results demonstrate the utility of a PROTAC to direct BRAF degradation and reveal that multi-driver oncogenesis renders some colorectal cancer cells resistant to BRAF-targeted treatment.
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Affiliation(s)
| | | | - Gongqin Sun
- Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA; (A.G.C.); (G.C.K.)
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Adashek JJ, Kato S, Sicklick JK, Lippman SM, Kurzrock R. Considering molecular alterations as pan-cancer tissue-agnostic targets. NATURE CANCER 2023; 4:1622-1626. [PMID: 38102355 PMCID: PMC11262846 DOI: 10.1038/s43018-023-00676-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2023]
Abstract
Owing to high response rates, the Food and Drug Administration has approved both gene- and immune-targeted drugs for tumor-agnostic, genomic biomarker-based indications, for lethal solid and blood cancers. We posit that current data support tissue-agnostic activity as a paradigm, rather than an exception to the rule.
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Affiliation(s)
- Jacob J Adashek
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Shumei Kato
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Jason K Sicklick
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
- Department of Surgery, Division of Surgical Oncology, University of California San Diego, UC San Diego Health, San Diego, CA, USA
- Department of Pharmacology, University of California San Diego, UC San Diego Health, San Diego, CA, USA
| | - Scott M Lippman
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Razelle Kurzrock
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA.
- WIN Consortium, Paris, France.
- University of Nebraska, Lincoln, NE, USA.
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Mohankumar K, Wright G, Kumaravel S, Shrestha R, Zhang L, Abdelrahim M, Chapkin RS, Safe S. Bis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion. Cancer Immunol Immunother 2023; 72:3985-3999. [PMID: 37847301 PMCID: PMC10700478 DOI: 10.1007/s00262-023-03530-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 08/14/2023] [Indexed: 10/18/2023]
Abstract
There is evidence that the orphan nuclear receptor 4A1 (NR4A1, Nur77) is overexpressed in exhausted CD8 + T cells and regulates PD-L1 in tumors. This study investigated the effects of potent bis-indole-derived NR4A1 antagonists on reversing T-cell exhaustion and downregulating PD-L1 in colon tumors/cells. NR4A1 antagonists inhibited colon tumor growth and downregulated expression of PD-L1 in mouse colon MC-38-derived tumors and cells. TILs from MC-38 cell-derived colon tumors and splenic lymphocytes exhibited high levels of the T-cell exhaustion markers including PD-1, 2B4, TIM3+ and TIGIT and similar results were observed in the spleen, and these were inhibited by NR4A1 antagonists. In addition, treatment with NR4A1 antagonists induced cytokine activation markers interferon γ, granzyme B and perforin mRNAs and decreased TOX, TOX2 and NFAT in TIL-derived CD8 + T cells. Thus, NR4A1 antagonists decrease NR4A1-dependent pro-oncogenic activity and PD-L1 expression in colon tumors and inhibit NR4A1-dependent T-cell exhaustion in TILs and spleen and represent a novel class of mechanism-based drugs that enhance immune surveillance in tumors.
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Affiliation(s)
- Kumaravel Mohankumar
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843, USA
| | - Gus Wright
- Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, 77843, USA
- TAMU Flow Cytometry Facility, Texas A&M University, College Station, TX, 77843, USA
| | - Subhashree Kumaravel
- Department of Medical Physiology, College of Medicine, Texas A&M University, College Station, TX, 77843, USA
| | - Rupesh Shrestha
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, USA
| | - Lei Zhang
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843, USA
| | - Maen Abdelrahim
- Houston Methodist Cancer Center, Institute of Academic Medicine and Weill Cornell Medical College, Houston, TX, 77030, USA
| | - Robert S Chapkin
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, USA
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843, USA.
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Liu C, Yu C, Song G, Fan X, Peng S, Zhang S, Zhou X, Zhang C, Geng X, Wang T, Cheng W, Zhu W. Comprehensive analysis of miRNA-mRNA regulatory pairs associated with colorectal cancer and the role in tumor immunity. BMC Genomics 2023; 24:724. [PMID: 38036953 PMCID: PMC10688136 DOI: 10.1186/s12864-023-09635-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/29/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND MicroRNA (miRNA) which can act as post-transcriptional regulators of mRNAs via base-pairing with complementary sequences within mRNAs is involved in processes of the complex interaction between immune system and tumors. In this research, we elucidated the profiles of miRNAs and target mRNAs expression and their associations with the phenotypic hallmarks of colorectal cancers (CRC) by integrating transcriptomic, immunophenotype, methylation, mutation and survival data. RESULTS We conducted the analysis of differential miRNA/mRNA expression profile by GEO, TCGA and GTEx databases and the correlation between miRNA and targeted mRNA by miRTarBase and TarBase. Then we detected using qRT-PCR and validated the diagnostic value of miRNA-mRNA regulator pairs by the ROC, calibration curve and DCA. Phenotypic hallmarks of regulatory pairs including tumor-infiltrating lymphocytes, tumor microenvironment, tumor mutation burden, global methylation and gene mutation were also described. The expression levels of miRNAs and target mRNAs were detected in 80 paired colon tissue samples. Ultimately, we picked up two pivotal regulatory pairs (miR-139-5p/ STC1 and miR-20a-5p/ FGL2) and verified the diagnostic value of the complex model which is the combination of 4 signatures above-mentioned in 3 testing GEO datasets and an external validation cohort. CONCLUSIONS We found that 2 miRNAs by targeting 2 metastasis-related mRNAs were correlated with tumor-infiltrating macrophages, HRAS, and BRAF gene mutation status. Our results established the diagnostic model containing 2 miRNAs and their respective targeted mRNAs to distinguish CRCs and normal controls and displayed their complex roles in CRC pathogenesis especially tumor immunity.
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Affiliation(s)
- Cheng Liu
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Chun Yu
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Guoxin Song
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China, Jiangsu
| | - Xingchen Fan
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China, Jiangsu
| | - Shuang Peng
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China, Jiangsu
| | - Shiyu Zhang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China, Jiangsu
| | - Xin Zhou
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China, Jiangsu
| | - Cheng Zhang
- Department of Science and Technology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China, Jiangsu
| | - Xiangnan Geng
- Department of Clinical Engineer, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China, Jiangsu
| | - Tongshan Wang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China, Jiangsu
| | - Wenfang Cheng
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
| | - Wei Zhu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China, Jiangsu.
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Xu Y, Wang G, Zheng X, Chang W, Fu J, Zhang T, Lin Q, Lv Y, Zhu Z, Tang W, Xu J. Treatment of metastatic colorectal cancer with BRAF V600E mutation: A multicenter real-world study in China. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:106981. [PMID: 37455182 DOI: 10.1016/j.ejso.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/30/2023] [Accepted: 07/08/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND BRAF V600E mutant-metastatic colorectal cancer (mCRC) is characterized by its short survival time. Treatment approaches vary depending on whether or not the metastases are initially resectable. The benefit of metastasectomy remains unclear, and the optimal first-line treatment is controversial. This study aimed to describe the prognosis of BRAF V600E mutant-mCRC, analyze the recurrence pattern in resectable patients, and explore the optimal first-line treatment for unresectable patients. METHODS Patients diagnosed with BRAF V600E mutant-mCRC between February 2014 and January 2022 in five hospitals were enrolled. Date on clinical and pathological characteristics, treatment features, and survival outcomes were collected. RESULTS Of the 220 included patients, 64 initially resectable patients had a significantly longer overall survival (OS) (37.07 vs. 20.20 months, P < 0.001) than initially unresectable patients. Of 156 unresectable patients, 54 received doublet (FOLFOX, XELOX or FOLFIRI) or triplet (FOLFOXIRI) chemotherapies (Chemo), 55 received Chemo plus Bevacizumab (Chemo+Bev), and 33 received vemurafenib plus cetuximab and irinotecan (VIC). The VIC regimen had a better progression-free survival (PFS) (12.70 months) than the Chemo (6.70 months, P < 0.001) and Chemo+Bev (8.8 months, P = 0.044) regimens. Patients treated with VIC had the best overall response rate (60.16%, P < 0.001), disease control rate (93.94%, P < 0.001) and conversional resection rate (24.24%, P = 0.003). CONCLUSIONS Metastasectomy is beneficial to the survival of patients with BRAF V600E mutant-mCRC. For initially unresectable patients, VIC as first-line therapy is associated with a better prognosis and efficacy than doublet and triplet chemotherapy with or without bevacizumab.
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Affiliation(s)
- Yuqiu Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guiying Wang
- Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China; The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Xuzhi Zheng
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Wenju Chang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jihong Fu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Tao Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qi Lin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yang Lv
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhehui Zhu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wentao Tang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Jianmin Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
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Sodir NM, Pathria G, Adamkewicz JI, Kelley EH, Sudhamsu J, Merchant M, Chiarle R, Maddalo D. SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment. Cancer Discov 2023; 13:2339-2355. [PMID: 37682219 PMCID: PMC10618746 DOI: 10.1158/2159-8290.cd-23-0383] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 06/20/2023] [Accepted: 07/27/2023] [Indexed: 09/09/2023]
Abstract
The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response. SIGNIFICANCE The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.
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Affiliation(s)
- Nicole M. Sodir
- Department of Translational Oncology, Genentech, South San Francisco, California
| | - Gaurav Pathria
- Department of Oncology Biomarker Development, Genentech, South San Francisco, California
| | | | - Elizabeth H. Kelley
- Department of Discovery Chemistry, Genentech, South San Francisco, California
| | - Jawahar Sudhamsu
- Department of Structural Biology, Genentech, South San Francisco, California
| | - Mark Merchant
- Department of Translational Oncology, Genentech, South San Francisco, California
| | - Roberto Chiarle
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Danilo Maddalo
- Department of Translational Oncology, Genentech, South San Francisco, California
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Matteucci L, Bittoni A, Gallo G, Ridolfi L, Passardi A. Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era? Cancers (Basel) 2023; 15:5189. [PMID: 37958363 PMCID: PMC10648369 DOI: 10.3390/cancers15215189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/21/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.
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Affiliation(s)
- Laura Matteucci
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Alessandro Bittoni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Graziana Gallo
- Operative Unit of Pathologic Anatomy, Azienda USL della Romagna, “Maurizio Bufalini” Hospital, 47521 Cesena, Italy
| | - Laura Ridolfi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
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43
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Lamichhane A, Luker GD, Agarwal S, Tavana H. Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells. Oncotarget 2023; 14:879-889. [PMID: 37791907 PMCID: PMC10549774 DOI: 10.18632/oncotarget.28517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 09/21/2023] [Indexed: 10/05/2023] Open
Abstract
Drug resistance is a major barrier against successful treatments of cancer patients. Gain of stemness under drug pressure is a major mechanism that renders treatments ineffective. Identifying approaches to target cancer stem cells (CSCs) is expected to improve treatment outcomes for patients. To elucidate the role of cancer stemness in resistance of colorectal cancer cells to targeted therapies, we developed spheroid cultures of patient-derived BRAFmut and KRASmut tumor cells and studied resistance mechanisms to inhibition of MAPK pathway through phenotypic and gene and protein expression analysis. We found that treatments enriched the expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 and activated PI3K/Akt pathway in cancer cells. We examined various combination treatments to block these activities and found that a triple combination against BRAF, EGFR, and MEK significantly reduced stemness and activities of oncogenic signaling pathways. This study demonstrates the feasibility of blocking stemness-mediated drug resistance and tumorigenic activities in colorectal cancer.
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Affiliation(s)
- Astha Lamichhane
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA
| | - Gary D. Luker
- Department of Radiology, Microbiology and Immunology, Biomedical Engineering, University of Michigan, Ann Arbor, MI 48105, USA
| | - Seema Agarwal
- Department of Pathology, Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, DC 20007, USA
| | - Hossein Tavana
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA
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44
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Chen W, Park JI. Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2. Int J Mol Sci 2023; 24:14837. [PMID: 37834284 PMCID: PMC10573597 DOI: 10.3390/ijms241914837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information.
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Affiliation(s)
| | - Jong-In Park
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
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45
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Yang M, Xu Z, Mi M, Ding Y, Pan Y, Yuan Y, Sun W, Weng S. CSCO guidelines for metastatic colorectal cancer: personalized medicine in clinical practice. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0211. [PMID: 37700433 PMCID: PMC10546093 DOI: 10.20892/j.issn.2095-3941.2023.0211] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 07/21/2023] [Indexed: 09/14/2023] Open
Affiliation(s)
- Mengyuan Yang
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Ziheng Xu
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Mi Mi
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Yuwei Ding
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Yuefen Pan
- Department of Medical Oncology, Huzhou Central Hospital, Huzhou 313000, China
| | - Ying Yuan
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou 310009, China
- Cancer Center of Zhejiang University, Hangzhou 310058, China
- Binjiang Institute of Zhejiang University, Hangzhou 310052, China
| | - Weijing Sun
- Department of Medical Oncology, The University of Kansas, School of Medicine, Lawrence, KS 66045, United States
| | - Shanshan Weng
- Department of Medical Oncology (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou 310009, China
- Cancer Center of Zhejiang University, Hangzhou 310058, China
- Binjiang Institute of Zhejiang University, Hangzhou 310052, China
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Hilhorst R, van den Berg A, Boender P, van Wezel T, Kievits T, de Wijn R, Ruijtenbeek R, Corver WE, Morreau H. Differentiating Benign from Malignant Thyroid Tumors by Kinase Activity Profiling and Dabrafenib BRAF V600E Targeting. Cancers (Basel) 2023; 15:4477. [PMID: 37760447 PMCID: PMC10527361 DOI: 10.3390/cancers15184477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/28/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Differentiated non-medullary thyroid cancer (NMTC) can be effectively treated by surgery followed by radioactive iodide therapy. However, a small subset of patients shows recurrence due to a loss of iodide transport, a phenotype frequently associated with BRAF V600E mutations. In theory, this should enable the use of existing targeted therapies specifically designed for BRAF V600E mutations. However, in practice, generic or specific drugs aimed at molecular targets identified by next generation sequencing (NGS) are not always beneficial. Detailed kinase profiling may provide additional information to help improve therapy success rates. In this study, we therefore investigated whether serine/threonine kinase (STK) activity profiling can accurately classify benign thyroid lesions and NMTC. We also determined whether dabrafenib (BRAF V600E-specific inhibitor), as well as sorafenib and regorafenib (RAF inhibitors), can differentiate BRAF V600E from non-BRAF V600E thyroid tumors. Using 21 benign and 34 malignant frozen thyroid tumor samples, we analyzed serine/threonine kinase activity using PamChip®peptide microarrays. An STK kinase activity classifier successfully differentiated malignant (26/34; 76%) from benign tumors (16/21; 76%). Of the kinases analyzed, PKC (theta) and PKD1 in particular, showed differential activity in benign and malignant tumors, while oncocytic neoplasia or Graves' disease contributed to erroneous classifications. Ex vivo BRAF V600E-specific dabrafenib kinase inhibition identified 6/92 analyzed peptides, capable of differentiating BRAF V600E-mutant from non-BRAF V600E papillary thyroid cancers (PTCs), an effect not seen with the generic inhibitors sorafenib and regorafenib. In conclusion, STK activity profiling differentiates benign from malignant thyroid tumors and generates unbiased hypotheses regarding differentially active kinases. This approach can serve as a model to select novel kinase inhibitors based on tissue analysis of recurrent thyroid and other cancers.
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Affiliation(s)
- Riet Hilhorst
- PamGene International BV, 5211 HH ‘s-Hertogenbosch, The Netherlands; (R.H.)
| | | | - Piet Boender
- PamGene International BV, 5211 HH ‘s-Hertogenbosch, The Netherlands; (R.H.)
| | - Tom van Wezel
- Leiden University Medical Center, 2333 ZA Leiden, The Netherlands (H.M.)
| | - Tim Kievits
- PamGene International BV, 5211 HH ‘s-Hertogenbosch, The Netherlands; (R.H.)
| | - Rik de Wijn
- PamGene International BV, 5211 HH ‘s-Hertogenbosch, The Netherlands; (R.H.)
| | - Rob Ruijtenbeek
- PamGene International BV, 5211 HH ‘s-Hertogenbosch, The Netherlands; (R.H.)
| | - Willem E. Corver
- Leiden University Medical Center, 2333 ZA Leiden, The Netherlands (H.M.)
| | - Hans Morreau
- Leiden University Medical Center, 2333 ZA Leiden, The Netherlands (H.M.)
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Unal U, Gov E. Drug Repurposing Analysis for Colorectal Cancer through Network Medicine Framework: Novel Candidate Drugs and Small Molecules. Cancer Invest 2023; 41:713-733. [PMID: 37682113 DOI: 10.1080/07357907.2023.2255672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 02/04/2023] [Accepted: 09/01/2023] [Indexed: 09/09/2023]
Abstract
This study aimed to reveal the drug-repurposing candidates for colorectal cancer (CRC) via drug-repurposing methods and network biology approaches. A novel, differentially co-expressed, highly interconnected, and co-regulated prognostic gene module was identified for CRC. Based on the gene module, polyethylene glycol (PEG), gallic acid, pyrazole, cordycepin, phenothiazine, pantoprazole, cysteamine, indisulam, valinomycin, trametinib, BRD-K81473043, AZD8055, dovitinib, BRD-A17065207, and tyrphostin AG1478 presented as drugs and small molecule candidates previously studied in the CRC. Lornoxicam, suxamethonium, oprelvekin, sirukumab, levetiracetam, sulpiride, NVP-TAE684, AS605240, 480743.cdx, HDAC6 inhibitor ISOX, BRD-K03829970, and L-6307 are proposed as novel drugs and small molecule candidates for CRC.
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Affiliation(s)
- Ulku Unal
- Department of Bioengineering, Adana Alparslan Türkeş Science and Technology University, Adana, Turkey
| | - Esra Gov
- Department of Bioengineering, Adana Alparslan Türkeş Science and Technology University, Adana, Turkey
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48
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Huang S, Ye J, Gao X, Huang X, Huang J, Lu L, Lu C, Li Y, Luo M, Xie M, Lin Y, Liang R. Progress of research on molecular targeted therapies for colorectal cancer. Front Pharmacol 2023; 14:1160949. [PMID: 37614311 PMCID: PMC10443711 DOI: 10.3389/fphar.2023.1160949] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 07/26/2023] [Indexed: 08/25/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies, accounting for approximately 10% of global cancer incidence and mortality. Approximately 20% of patients with CRC present metastatic disease (mCRC) at the time of diagnosis. Moreover, up to 50% of patients with localized disease eventually metastasize. mCRC encompasses a complex cascade of reactions involving multiple factors and processes, leading to a diverse array of molecular mechanisms. Improved comprehension of the pathways underlying cancer cell development and proliferation, coupled with the accessibility of relevant targeted agents, has propelled advancements in CRC treatment, ultimately leading to enhanced survival rates. Mutations in various pathways and location of the primary tumor in CRC influences the efficacy of targeted agents. This review summarizes available targeted agents for different CRC pathways, with a focus on recent advances in anti-angiogenic and anti-epidermal growth factor receptor agents, BRAF mutations, and human epidermal growth factor receptor 2-associated targeted agents.
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Affiliation(s)
- Shilin Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xing Gao
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xi Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Julu Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lu Lu
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Cheng Lu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yongqiang Li
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Min Luo
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Mingzhi Xie
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yan Lin
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Rong Liang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
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Saoudi González N, Salvà F, Ros J, Baraibar I, Rodríguez-Castells M, García A, Alcaráz A, Vega S, Bueno S, Tabernero J, Elez E. Unravelling the Complexity of Colorectal Cancer: Heterogeneity, Clonal Evolution, and Clinical Implications. Cancers (Basel) 2023; 15:4020. [PMID: 37627048 PMCID: PMC10452468 DOI: 10.3390/cancers15164020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023] Open
Abstract
Colorectal cancer (CRC) is a global health concern and a leading cause of death worldwide. The disease's course and response to treatment are significantly influenced by its heterogeneity, both within a single lesion and between primary and metastatic sites. Biomarkers, such as mutations in KRAS, NRAS, and BRAF, provide valuable guidance for treatment decisions in patients with metastatic CRC. While high concordance exists between mutational status in primary and metastatic lesions, some heterogeneity may be present. Circulating tumor DNA (ctDNA) analysis has proven invaluable in identifying genetic heterogeneity and predicting prognosis in RAS-mutated metastatic CRC patients. Tumor heterogeneity can arise from genetic and non-genetic factors, affecting tumor development and response to therapy. To comprehend and address clonal evolution and intratumoral heterogeneity, comprehensive genomic studies employing techniques such as next-generation sequencing and computational analysis are essential. Liquid biopsy, notably through analysis of ctDNA, enables real-time clonal evolution and treatment response monitoring. However, challenges remain in standardizing procedures and accurately characterizing tumor subpopulations. Various models elucidate the origin of CRC heterogeneity, highlighting the intricate molecular pathways involved. This review focuses on intrapatient cancer heterogeneity and genetic clonal evolution in metastatic CRC, with an emphasis on clinical applications.
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Affiliation(s)
- Nadia Saoudi González
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Francesc Salvà
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Javier Ros
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Iosune Baraibar
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Marta Rodríguez-Castells
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Ariadna García
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
| | - Adriana Alcaráz
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Sharela Vega
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Sergio Bueno
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Josep Tabernero
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Elena Elez
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
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50
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Dao V, Heestand G. Beyond EGFR inhibitors in advanced colorectal cancer: Targeting BRAF and HER2. Curr Probl Cancer 2023; 47:100960. [PMID: 37285606 DOI: 10.1016/j.currproblcancer.2023.100960] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/14/2023] [Accepted: 04/18/2023] [Indexed: 06/09/2023]
Abstract
The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild-type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates remain limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplification/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strategies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies targeting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, often in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement.
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Affiliation(s)
- Vinh Dao
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California
| | - Gregory Heestand
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
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