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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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2
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Mo C, Chadha B, Kuang C. An Evolving Landscape: New Therapies for Metastatic Colorectal Cancer. Clin Colorectal Cancer 2024; 23:337-345. [PMID: 39332920 PMCID: PMC11608151 DOI: 10.1016/j.clcc.2024.08.003] [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: 07/20/2024] [Revised: 08/18/2024] [Accepted: 08/21/2024] [Indexed: 09/29/2024]
Abstract
Substantial progress is being made in the development of novel therapies directed against colorectal cancer. The discovery of various molecular markers and advances in tumor profiling have facilitated the development of new targeted agents and immunotherapy. Not only have these drugs improved progression-free survival and even overall survival in some cases, but their related outcomes have also raised questions as to how to best combine or sequence therapies for even greater efficacy. Furthermore, we are beginning to understand how these combination therapies may yield for greater therapeutic response for patients with microsatellite stable colorectal cancer for which there is much need for improvement. In this article, we review recent trial data and explore the outcomes of various targeted therapies and immunotherapies for patient with advanced colorectal cancer.
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Affiliation(s)
- Christiana Mo
- Department of Oncology, Montefiore Einstein, Bronx, NY; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY
| | - Bhawneet Chadha
- Department of Oncology, Montefiore Einstein, Bronx, NY; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY
| | - Chaoyuan Kuang
- Department of Oncology, Montefiore Einstein, Bronx, NY; Department of Molecular Pharmacology, Montefiore Einstein, Bronx, NY.
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3
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Song Y, Chen M, Wei Y, Ma X, Shi H. Signaling pathways in colorectal cancer implications for the target therapies. MOLECULAR BIOMEDICINE 2024; 5:21. [PMID: 38844562 PMCID: PMC11156834 DOI: 10.1186/s43556-024-00178-y] [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: 07/10/2023] [Accepted: 02/29/2024] [Indexed: 06/09/2024] Open
Abstract
Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.
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Affiliation(s)
- Yanlin Song
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Ming Chen
- West China School of Medicine, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Yuhao Wei
- West China School of Medicine, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Huashan Shi
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
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4
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Mukhtar AB, Morgan HJ, Gibbs A, Davies GE, Lovatt C, Patel GK. Targeting CD20-expressing malignant melanoma cells augments BRAF inhibitor killing. Br J Dermatol 2024; 190:729-739. [PMID: 38288865 DOI: 10.1093/bjd/ljad502] [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: 09/17/2022] [Revised: 12/08/2023] [Indexed: 04/19/2024]
Abstract
BACKGROUND Mutant BRAF targeted therapies remain a standard of care for the treatment of metastatic malignant melanoma (MM); however, high initial response rates are tempered by the persistence of residual MM cells that eventually lead to disease recurrence and mortality. As MM recurrence during targeted therapy can present with the simultaneous occurrence of multiple tumour nodules at the original body sites, we hypothesized the presence of an intrinsically resistant MM cell subpopulation. OBJECTIVES To identify an MM cell subpopulation that is intrinsically resistant to targeted therapy and possibly responsible for MM recurrence. METHODS Using melanoma cell lines, we defined culture conditions for the reproducible three-dimensional growth of melanospheres to investigate putative cancer stem cell populations. We undertook RNA sequencing and bioinformatic analysis to characterize cell populations between adherent and nonadherent culture, and cells expressing or not expressing CD20. Furthermore, we defined an in vitro assay to evaluate the killing of melanoma cancer stem cells as a therapeutic test using combination therapies targeting driver mutation and CD20. RESULTS We described the culture conditions that promote MM cells to form melanospheres with a reproducible colony-forming efficiency rate of 0.3-1.3%. RNA sequencing of melanosphere vs. conventional MM cell cultures (n = 6), irrespective of the BRAF mutation status, showed that melanosphere formation was associated with growth and differentiation transcriptional signatures resembling MM tumours. Importantly, melanosphere formation also led to the emergence of a CD20+ MM cell subpopulation, similar to that observed in primary human MM tumours. CD20+ MM cells were resistant to BRAF inhibitor therapy and, consistent with this finding, demonstrated a Forkhead box protein M1 transcriptomic profile (n = 6). Combining BRAF inhibitor and anti-CD20 antibody treatment led to the additional killing of previously resistant CD20+ BRAF mutant MM cells. CONCLUSIONS In patients with MM that harbour a CD20+ subpopulation, combined therapy with BRAF inhibitor and anti-CD20 antibody could potentially kill residual MM cells and prevent disease recurrence.
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Affiliation(s)
- Abdullahi B Mukhtar
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, UK
| | - Huw J Morgan
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, UK
| | - Alex Gibbs
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, UK
| | - Gemma E Davies
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, UK
| | - Charlotte Lovatt
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, UK
| | - Girish K Patel
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, UK
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5
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Cavallo MR, Yo JC, Gallant KC, Cunanan CJ, Amirfallah A, Daniali M, Sanders AB, Aplin AE, Pribitkin EA, Hartsough EJ. Mcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma. Cell Death Discov 2024; 10:175. [PMID: 38622136 PMCID: PMC11018618 DOI: 10.1038/s41420-024-01945-0] [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: 04/03/2023] [Revised: 03/29/2024] [Accepted: 04/05/2024] [Indexed: 04/17/2024] Open
Abstract
Papillary thyroid carcinoma (PTC) is the most frequent form of thyroid cancer. PTC commonly presents with mutations of the serine/threonine kinase BRAF (BRAFV600E), which drive ERK1/2 pathway activation to support growth and suppress apoptosis. PTC patients often undergo surgical resection; however, since the average age of PTC patients is under 50, adverse effects associated with prolonged maintenance therapy following total thyroidectomy are a concern. The development of mutant-selective BRAF inhibitors (BRAFi), like vemurafenib, has been efficacious in patients with metastatic melanoma, but the response rate is low for mutant BRAF PTC patients. Here, we assay the therapeutic response of BRAFi in a panel of human PTC cell lines and freshly biopsied patient samples. We observed heterogeneous responses to BRAFi, and multi-omic comparisons between susceptible and resistant mutant BRAF PTC revealed overrepresented stress response pathways and the absence of compensatory RTK activation - features that may underpin innate resistance. Importantly, resistant cell lines and patient samples had increased hallmarks of failed apoptosis; a cellular state defined by sublethal caspase activation and DNA damage. Further analysis suggests that the failed apoptotic phenotypes may have features of "minority mitochondrial outer membrane permeabilization (MOMP)" - a stress-related response characterized by fragmented and porous mitochondria known to contribute to cancer aggressiveness. We found that cells presenting with minority MOMP-like phenotypes are dependent on the apoptotic regulator, Mcl-1, as treatment with the Mcl-1 inhibitor, AZD5991, potently induced cell death in resistant cells. Furthermore, PI3K/AKT inhibitors sensitized resistant cells to BRAFi; an effect that was at least in part associated with reduced Mcl-1 levels. Together, these data implicate minority MOMP as a mechanism associated with intrinsic drug resistance and underscore the benefits of targeting Mcl-1 in mutant BRAF PTC.
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Affiliation(s)
- Maria R Cavallo
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Jacob C Yo
- Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Kayla C Gallant
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Camille J Cunanan
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Amirali Amirfallah
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Marzieh Daniali
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Alyssa B Sanders
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Andrew E Aplin
- Sidney Kimmel Cancer Center, Philadelphia, PA, 19107, USA
- Departments of Pharmacology, Physiology and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Edmund A Pribitkin
- Departments of Otolargynology-Head & Neck Surgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Edward J Hartsough
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
- Sidney Kimmel Cancer Center, Philadelphia, PA, 19107, USA.
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6
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Xing YL, Panovska D, Petritsch CK. Successes and challenges in modeling heterogeneous BRAF V600E mutated central nervous system neoplasms. Front Oncol 2023; 13:1223199. [PMID: 37920169 PMCID: PMC10619673 DOI: 10.3389/fonc.2023.1223199] [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: 05/15/2023] [Accepted: 09/18/2023] [Indexed: 11/04/2023] Open
Abstract
Central nervous system (CNS) neoplasms are difficult to treat due to their sensitive location. Over the past two decades, the availability of patient tumor materials facilitated large scale genomic and epigenomic profiling studies, which have resulted in detailed insights into the molecular underpinnings of CNS tumorigenesis. Based on results from these studies, CNS tumors have high molecular and cellular intra-tumoral and inter-tumoral heterogeneity. CNS cancer models have yet to reflect the broad diversity of CNS tumors and patients and the lack of such faithful cancer models represents a major bottleneck to urgently needed innovations in CNS cancer treatment. Pediatric cancer model development is lagging behind adult tumor model development, which is why we focus this review on CNS tumors mutated for BRAFV600E which are more prevalent in the pediatric patient population. BRAFV600E-mutated CNS tumors exhibit high inter-tumoral heterogeneity, encompassing clinically and histopathological diverse tumor types. Moreover, BRAFV600E is the second most common alteration in pediatric low-grade CNS tumors, and low-grade tumors are notoriously difficult to recapitulate in vitro and in vivo. Although the mutation predominates in low-grade CNS tumors, when combined with other mutations, most commonly CDKN2A deletion, BRAFV600E-mutated CNS tumors are prone to develop high-grade features, and therefore BRAFV600E-mutated CNS are a paradigm for tumor progression. Here, we describe existing in vitro and in vivo models of BRAFV600E-mutated CNS tumors, including patient-derived cell lines, patient-derived xenografts, syngeneic models, and genetically engineered mouse models, along with their advantages and shortcomings. We discuss which research gaps each model might be best suited to answer, and identify those areas in model development that need to be strengthened further. We highlight areas of potential research focus that will lead to the heightened predictive capacity of preclinical studies, allow for appropriate validation, and ultimately improve the success of "bench to bedside" translational research.
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Affiliation(s)
| | | | - Claudia K. Petritsch
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
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7
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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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8
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Car I, Dittmann A, Vasieva O, Bočkor L, Grbčić P, Piteša N, Klobučar M, Kraljević Pavelić S, Sedić M. Ezrin Inhibition Overcomes Acquired Resistance to Vemurafenib in BRAFV600E-Mutated Colon Cancer and Melanoma Cells In Vitro. Int J Mol Sci 2023; 24:12906. [PMID: 37629086 PMCID: PMC10454476 DOI: 10.3390/ijms241612906] [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: 06/07/2023] [Revised: 08/14/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Despite the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach. Bioinformatic analysis of obtained proteomics data indicated actin-cytoskeleton linker protein ezrin as a highly ranked protein significantly associated with vemurafenib resistance whose overexpression in the resistant cells was additionally confirmed at the gene and protein level. Ezrin inhibition by NSC305787 increased anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant cells in an additive manner, which was accompanied by downregulation of CD44 expression and inhibition of AKT/c-Myc activities. We also detected an increased ezrin expression in vemurafenib-resistant melanoma cells harbouring the BRAFV600E mutation. Importantly, ezrin inhibition potentiated anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant melanoma cells in a synergistic manner. Altogether, our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying the BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers.
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Affiliation(s)
- Iris Car
- Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, Croatia; (I.C.); (L.B.); (M.K.)
| | - Antje Dittmann
- Functional Genomics Center Zurich, ETH Zurich, Winterthurerstr. 190, Y59 H38, 8057 Zurich, Switzerland;
| | - Olga Vasieva
- INGENET Ltd., 27 Market Street, Hoylake, Wirral CH47 2BG, UK;
| | - Luka Bočkor
- Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, Croatia; (I.C.); (L.B.); (M.K.)
| | - Petra Grbčić
- Faculty of Medicine, Juraj Dobrila University of Pula, Zagrebačka ul. 30, 52100 Pula, Croatia;
| | - Nikolina Piteša
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička Cesta 54, 10000 Zagreb, Croatia;
| | - Marko Klobučar
- Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, Croatia; (I.C.); (L.B.); (M.K.)
| | | | - Mirela Sedić
- Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, Croatia; (I.C.); (L.B.); (M.K.)
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9
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Napolitano S, Woods M, Lee HM, De Falco V, Martini G, Della Corte CM, Martinelli E, Famiglietti V, Ciardiello D, Anderson A, Fowlkes NW, Villareal OE, Sorokin A, Kanikarla P, Coker O, Morris V, Altucci L, Tabernero J, Troiani T, Ciardiello F, Kopetz S. Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer. Clin Cancer Res 2023; 29:2299-2309. [PMID: 37040395 PMCID: PMC10261917 DOI: 10.1158/1078-0432.ccr-22-3894] [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: 12/21/2022] [Revised: 03/14/2023] [Accepted: 04/07/2023] [Indexed: 04/12/2023]
Abstract
PURPOSE Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC. EXPERIMENTAL DESIGN We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed. RESULTS Antitumor activity of either FOLFIRI or E+C was better as first-line treatment as compared with second-line, with partial cross-resistance seen between a cytotoxic regimen and targeted therapy with an average 62% loss of efficacy for FOLFIRI after E+C and a 45% loss of efficacy of E+C after FOLFIRI (P < 0.001 for both). FOLFIRI-treated models had upregulation of epithelial-mesenchymal transition (EMT) and MAPK pathway activation, where E+C treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared with E+C or to chemotherapy alone. Furthermore, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C ± 5-FU as maintenance therapy, was the most effective strategy for long-term disease control. CONCLUSIONS These results support the combination of cytotoxic chemotherapy and molecular-targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.
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Affiliation(s)
- Stefania Napolitano
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy
| | - Melanie Woods
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hey Min Lee
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vincenzo De Falco
- 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
| | - Carminia Maria Della Corte
- 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
| | - Vincenzo Famiglietti
- 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
| | - Amanda Anderson
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Natalie Wall Fowlkes
- Veterinary Medicine & Surgery Department, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Oscar Eduardo Villareal
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexey Sorokin
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Preeti Kanikarla
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Olu Coker
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Van Morris
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lucia Altucci
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy
| | - Josep Tabernero
- Medical Oncology Department, Vall d' Hebron Hospital Campus, Barcelona, Spain
- Institute of Oncology, University of Vic/Central University of Catalonia, Barcelona, Spain
- Oncology Institute of Barcelona-Quironsalud, Biomedical Research Center in Cancer, Barcelona, Spain
| | - 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
| | - Scott Kopetz
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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10
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Morimoto Y, Yamashita N, Hirose H, Fushimi A, Haratake N, Daimon T, Bhattacharya A, Ahmad R, Suzuki Y, Takahashi H, Kufe DW. MUC1-C is necessary for SHP2 activation and BRAF inhibitor resistance in BRAF(V600E) mutant colorectal cancer. Cancer Lett 2023; 559:216116. [PMID: 36878307 PMCID: PMC10408991 DOI: 10.1016/j.canlet.2023.216116] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/19/2023] [Accepted: 03/02/2023] [Indexed: 03/07/2023]
Abstract
Colorectal cancers (CRCs) harboring the BRAF(V600E) mutation are associated with aggressive disease and resistance to BRAF inhibitors by feedback activation of the receptor tyrosine kinase (RTK)→RAS→MAPK pathway. The oncogenic MUC1-C protein promotes progression of colitis to CRC; whereas there is no known involvement of MUC1-C in BRAF(V600E) CRCs. The present work demonstrates that MUC1 expression is significantly upregulated in BRAF(V600E) vs wild-type CRCs. We show that BRAF(V600E) CRC cells are dependent on MUC1-C for proliferation and BRAF inhibitor (BRAFi) resistance. Mechanistically, MUC1-C integrates induction of MYC in driving cell cycle progression with activation of the SHP2 phosphotyrosine phosphatase, which enhances RTK-mediated RAS→ERK signaling. We demonstrate that targeting MUC1-C genetically and pharmacologically suppresses (i) activation of MYC, (ii) induction of the NOTCH1 stemness factor, and (iii) the capacity for self-renewal. We also show that MUC1-C associates with SHP2 and is required for SHP2 activation in driving BRAFi-induced feedback of ERK signaling. In this way, targeting MUC1-C in BRAFi-resistant BRAF(V600E) CRC tumors inhibits growth and sensitizes to BRAF inhibition. These findings demonstrate that MUC1-C is a target for the treatment of BRAF(V600E) CRCs and for reversing their resistance to BRAF inhibitors by suppressing the feedback MAPK pathway.
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Affiliation(s)
| | - Nami Yamashita
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Haruka Hirose
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Atsushi Fushimi
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Naoki Haratake
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Tatsuaki Daimon
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Rehan Ahmad
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Yozo Suzuki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Donald W Kufe
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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11
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Pingili D, Svum P, Nulgumnalli Manjunathaiah R. Design, Synthesis, In‐silico Studies and Antiproliferative Evaluation of Novel Indazole Derivatives as Small Molecule Inhibitors of B‐Raf. ChemistrySelect 2023. [DOI: 10.1002/slct.202300291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Affiliation(s)
- Divya Pingili
- Department of Pharmaceutical Chemistry Sri Venkateshwara College of Pharmacy Madhapur, Hyderabad 500081 Telangana India
- Department of Pharmacy Jawaharlal Nehru Technological University, postCode/>533003 Kakinada Andhrapradesh India
| | - Prasad Svum
- Department of Pharmacy Jawaharlal Nehru Technological University, postCode/>533003 Kakinada Andhrapradesh India
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12
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Mozammel N, Amini M, Baradaran B, Mahdavi SZB, Hosseini SS, Mokhtarzadeh A. The function of miR-145 in colorectal cancer progression; an updated review on related signaling pathways. Pathol Res Pract 2023; 242:154290. [PMID: 36621158 DOI: 10.1016/j.prp.2022.154290] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 12/28/2022]
Abstract
MicroRNAs (miRNA) are a broad class of small, highly conserved non-coding RNAs that largely influence gene expression after transcription through binding to various target mRNAs. miRNAs are frequently dysregulated in a wide array of human cancers, possessing great value as diagnostic and therapeutic targets. miR-145, as promising tumor suppressor miRNA, also exhibits deregulated expression levels in human malignancies and participates in various processes, including cell proliferation, apoptosis, migration and differentiation. In particular, miR-145 has been shown to be downregulated in colorectal cancer (CRC), which in turn leads to cell growth, invasion, metastasis and drug resistance. Furthermore, miR-145 is involved in the regulation of multiple tumor specific signaling pathways, such as KRAS and P53 signaling by targeting various genes through colorectal tumorigenesis. Therefore, considering its diagnostic and therapeutic potential, it was aimed to present the recent finding focusing on miR-145 functions to better understand its involvement in CRC incidence and progression through interplay with various signaling pathways. This study is based on articles indexed in PubMed and Google scholar until 2021.
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Affiliation(s)
- Nazila Mozammel
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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13
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Ruiz-Saenz A, Atreya CE, Wang C, Pan B, Dreyer CA, Brunen D, Prahallad A, Muñoz DP, Ramms DJ, Burghi V, Spassov DS, Fewings E, Hwang YC, Cowdrey C, Moelders C, Schwarzer C, Wolf DM, Hann B, VandenBerg SR, Shokat K, Moasser MM, Bernards R, Gutkind JS, van 't Veer LJ, Coppé JP. A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAF V600E colorectal tumors. NATURE CANCER 2023; 4:240-256. [PMID: 36759733 PMCID: PMC9970872 DOI: 10.1038/s43018-022-00508-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 12/21/2022] [Indexed: 02/11/2023]
Abstract
BRAFV600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF-MEK-EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinases are systematically activated in BRAFV600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through β-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E2 loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF + EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAFV600E CRC.
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Affiliation(s)
- Ana Ruiz-Saenz
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Departments of Cell Biology & Medical Oncology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Chloe E Atreya
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Changjun Wang
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Bo Pan
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Courtney A Dreyer
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Diede Brunen
- Division of Molecular Carcinogenesis and Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Anirudh Prahallad
- Division of Molecular Carcinogenesis and Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Denise P Muñoz
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Dana J Ramms
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.,Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Valeria Burghi
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.,Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Danislav S Spassov
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
| | - Eleanor Fewings
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Institute for Computational Biomedicine, Heidelberg, Germany
| | - Yeonjoo C Hwang
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Cynthia Cowdrey
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Christina Moelders
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Cecilia Schwarzer
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Denise M Wolf
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Byron Hann
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Scott R VandenBerg
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Kevan Shokat
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Mark M Moasser
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - René Bernards
- Division of Molecular Carcinogenesis and Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - J Silvio Gutkind
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.,Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Laura J van 't Veer
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Jean-Philippe Coppé
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
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14
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Liu Y, Song F, Li Z, Chen L, Xu Y, Sun H, Chang Y. A comprehensive tool for tumor precision medicine with pharmaco-omics data analysis. Front Pharmacol 2023; 14:1085765. [PMID: 36713829 PMCID: PMC9878337 DOI: 10.3389/fphar.2023.1085765] [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: 10/31/2022] [Accepted: 01/04/2023] [Indexed: 01/14/2023] Open
Abstract
Background: Cancer precision medicine is an effective strategy to fight cancers by bridging genomics and drug discovery to provide specific treatment for patients with different genetic characteristics. Although some public databases and modelling frameworks have been developed through studies on drug response, most of them only considered the ramifications of the drug on the cell line and the effects on the patient still require a huge amount of work to integrate data from various databases and calculations, especially concerning precision treatment. Furthermore, not only efficacy but also the adverse effects of drugs on patients should be taken into account during cancer treatment. However, the adverse effects as essential indicators of drug safety assessment are always neglected. Method: A holistic estimation explores various drugs' efficacy levels by calculating their potency both in reversing and enhancing cancer-associated gene expression change. And a method for bridging the gap between cell culture and living tissue estimates the effectiveness of a drug on individual patients through the mappings of various cell lines to each person according to their genetic mutation similarities. Result: We predicted the efficacy of FDA-recommended drugs, taking into account both efficacy and toxicity, and obtained consistent results. We also provided an intuitive and easy-to-use web server called DBPOM (http://www.dbpom.net/, a comprehensive database of pharmaco-omics for cancer precision medicine), which not only integrates the above methods but also provides calculation results on more than 10,000 small molecule compounds and drugs. As a one-stop web server, clinicians and drug researchers can also analyze the overall effect of a drug or a drug combination on cancer patients as well as the biological functions that they target. DBPOM is now public, free to use with no login requirement, and contains all the data and code. Conclusion: Both the positive and negative effects of drugs during precision treatment are essential for practical application of drugs. DBPOM based on the two effects will become a vital resource and analysis platform for drug development, drug mechanism studies and the discovery of new therapies.
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Affiliation(s)
- Yijun Liu
- School of Artificial Intelligence, Jilin University, Changchun, China
| | - Fuhu Song
- School of Artificial Intelligence, Jilin University, Changchun, China
| | - Zhi Li
- Medical Oncology Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Liang Chen
- Department of Computer Science, College of Engineering, Shantou University, Shantou, China,Key Laboratory of Intelligent Manufacturing Technology of Ministry of Education, Shantou University, Shantou, China
| | - Ying Xu
- Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, The University of Georgia, Athens, GA, United States
| | - Huiyan Sun
- School of Artificial Intelligence, Jilin University, Changchun, China,International Center of Future Science, Jilin University, Changchun, China,*Correspondence: Huiyan Sun, ; Yi Chang,
| | - Yi Chang
- School of Artificial Intelligence, Jilin University, Changchun, China,International Center of Future Science, Jilin University, Changchun, China,*Correspondence: Huiyan Sun, ; Yi Chang,
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15
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Yerlikaya A, Zeren S. Molecular Pathways, Targeted Therapies, and Proteomic Investigations of Colorectal Cancer. Curr Mol Med 2023; 23:2-12. [PMID: 34951572 DOI: 10.2174/1566524022666211224120614] [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: 07/29/2021] [Revised: 11/11/2021] [Accepted: 11/25/2021] [Indexed: 12/16/2022]
Abstract
According to the GLOBOCAN 2020 data, colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death. The risk factors for colorectal cancer include a diet abundant with fat, refined carbohydrates, animal protein, low fiber content, alcoholism, obesity, long-term cigarette smoking, low physical activity, and aging. Colorectal carcinomas are classified as adenocarcinoma, neuroendocrine, squamous cell, adenosquamous, spindle cell, and undifferentiated carcinomas. In addition, many variants of colorectal carcinomas have been recently distinguished based on histological, immunological, and molecular characteristics. Recently developed targeted molecules in conjunction with standard chemotherapeutics or immune checkpoint inhibitors provide promising treatment protocols for colorectal cancer. However, the benefit of targeted therapies is strictly dependent on the mutational status of signaling molecules (e.g., KRAS) or mismatch repair systems. Here it is aimed to provide a comprehensive view of colorectal cancer types, molecular pathways associated, recently developed targeted therapies, as well as proteomic investigations applied to colorectal cancer for the discovery of novel biomarkers and new targets for treatment protocols.
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Affiliation(s)
- Azmi Yerlikaya
- Department of Medical Biology, Faculty of Medicine, Kutahya Health Sciences University, Kutahya, Turkey
| | - Sezgin Zeren
- Department of General Surgery, Faculty of Medicine, Kutahya Health Sciences University, Kutahya, Turkey
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16
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Recent and Future Strategies to Overcome Resistance to Targeted Therapies and Immunotherapies in Metastatic Colorectal Cancer. J Clin Med 2022; 11:jcm11247523. [PMID: 36556139 PMCID: PMC9783354 DOI: 10.3390/jcm11247523] [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: 11/02/2022] [Revised: 12/06/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide, and 20% of patients with CRC present at diagnosis with metastases. The treatment of metastatic CRC is based on a fluoropyrimidine-based chemotherapy plus additional agents such as oxaliplatin and irinotecan. To date, on the basis of the molecular background, targeted therapies (e.g., monoclonal antibodies against epidermal growth factor receptor or inhibiting angiogenesis) are administered to improve the treatment of metastatic CRC. In addition, more recently, immunological agents emerged as effective in patients with a defective mismatch repair system. The administration of targeted therapies and immunotherapy lead to a significant increase in the survival of patients; however these drugs do not always prove effective. In most cases the lack of effectiveness is due to the development of primary resistance, either a resistance-inducing factor is already present before treatment or resistance is acquired when it occurs after treatment initiation. In this review we describe the most relevant targeted therapies and immunotherapies and expand on the reasons for resistance to the different approved or under development targeted drugs. Then we showed the possible mechanisms and drugs that may lead to overcoming the primary or acquired resistance in metastatic CRC.
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17
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Lamichhane A, Shahi Thakuri P, Singh S, Rafsanjani Nejad P, Heiss J, Luker GD, Tavana H. Therapeutic Targeting of Cancer Stem Cells Prevents Resistance of Colorectal Cancer Cells to MEK Inhibition. ACS Pharmacol Transl Sci 2022; 5:724-734. [PMID: 36110381 PMCID: PMC9469186 DOI: 10.1021/acsptsci.1c00257] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Indexed: 11/30/2022]
Abstract
Drug resistance is a leading cause for the failure of cancer treatments. Plasticity of cancer cells to acquire stem cell-like properties enables them to escape drug toxicity through different adaptive mechanisms. Eliminating cancer stem cells (CSCs) can potentially improve treatment outcomes for patients. To determine the role of CSCs in resistance of colorectal cancer cells to targeted therapies and identify treatment strategies, we treated spheroids of BRAFmut and KRASmut colorectal cancer cells with inhibitors of the mitogen-activated protein kinase pathway and studied resistance mechanisms through gene and protein expression analyses. We found that treatments activated several oncogenic pathways and expression of CSC markers CD166 and ALDH1A3. We identified a specific combination treatment using trametinib and mithramycin A to simultaneously inhibit the CSC phenotype and activities of several pathways in cancer cells. This study demonstrates the feasibility of therapeutic targeting of CSCs as a strategy to block tumorigenic activities of cancer cells.
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Affiliation(s)
- Astha Lamichhane
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Pradip Shahi Thakuri
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Sunil Singh
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Pouria Rafsanjani Nejad
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Jacob Heiss
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Gary D. Luker
- Department
of Radiology, Microbiology and Immunology, Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48105, United States
| | - Hossein Tavana
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
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18
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Tsimberidou AM, Müller P, Ji Y. Innovative trial design in precision oncology. Semin Cancer Biol 2022; 84:284-292. [PMID: 33022355 DOI: 10.1016/j.semcancer.2020.09.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 09/09/2020] [Indexed: 01/01/2023]
Abstract
Genomic profiling technologies have enabled the development of targeted therapies designed to target specific biomarkers and molecular pathways involved in the pathophysiology of tumor initiation, metastasis, and drug resistance. In recent years, clinical trials with innovative design focus on the development of novel agents based on specific patient molecular alterations or other tumor characteristics and include patients with heterogenous tumor types. Precision oncology studies with innovative design associated with novel dose-finding approaches and data analysis focusing on subgroups of patients are characteristic of master protocols. Real-world data, patient-reported outcomes, and N-of-1 trials enhance the knowledge base of evidence to deliver personalized treatment to patients. Master protocols accelerate drug development by enabling simultaneous multiple sub-studies that match the patient's tumor molecular profile with experimental treatment arms. However, the increased flexibility of precision oncology trials is often associated with small subpopulations of patients, which may be underpowered to draw statistically robust conclusions. Despite their limitations, innovative clinical trials continue to rapidly translate the emerging discoveries of novel drugs into unprecedented clinical outcomes in patients with cancer and to accelerate the implementation of precision oncology.
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Affiliation(s)
- Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics, Phancise I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, Unit 455, Houston, TX 77030, United States.
| | - Peter Müller
- Department of Mathematics, The University of Texas at Austin, 1 University Station, C1200, Austin, TX 78712, United States.
| | - Yuan Ji
- Department of Public Health Sciences, 5841 S. Maryland Ave, MC2000, Chicago, IL 60637, United States.
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19
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España MS. Treatment of advanced BRAF-mutated colorectal cancer: where we are and where we are going. Clin Colorectal Cancer 2022; 21:71-79. [DOI: 10.1016/j.clcc.2022.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 01/16/2022] [Accepted: 01/24/2022] [Indexed: 11/03/2022]
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20
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Pashirzad M, Khorasanian R, Fard MM, Arjmand MH, Langari H, Khazaei M, Soleimanpour S, Rezayi M, Ferns GA, Hassanian SM, Avan A. The Therapeutic Potential of MAPK/ERK Inhibitors in the Treatment of Colorectal Cancer. Curr Cancer Drug Targets 2021; 21:932-943. [PMID: 34732116 DOI: 10.2174/1568009621666211103113339] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 05/16/2021] [Accepted: 08/24/2021] [Indexed: 11/22/2022]
Abstract
The MAPK/ERK signaling pathway regulates cancer cell proliferation, apoptosis, inflammation, angiogenesis, metastasis and drug resistance. Mutations and up-regulation of components of the MAPK/ERK signaling pathway, as well as over-activation of this critical signaling pathway, are frequently observed in colorectal carcinomas. Targeting the MAPK/ERK signaling pathway, using specific pharmacological inhibitors, elicits potent anti-tumor effects, supporting the therapeutic potential of these inhibitors in the treatment of CRC. Several drugs have recently been developed for the inhibition of the MEK/ERK pathway in preclinical and clinical settings, such as MEK162 and MK-2206. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity for the treatment of this malignancy. This review summarizes the current knowledge on the role of the MAPK/ERK signaling pathway in the pathogenesis of CRC and the potential clinical value of synthetic inhibitors of this pathway in preventing CRC progression for a better understanding, and hence, better management of colorectal cancer.
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Affiliation(s)
- Mehran Pashirzad
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Reihaneh Khorasanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Maryam Mahmoudi Fard
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Mohammad-Hassan Arjmand
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord. Iran
| | - Hadis Langari
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord. Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Saman Soleimanpour
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Majid Rezayi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord. Iran
| | - Gordon A Ferns
- Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO. United States
| | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad. Iran
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21
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Grbčić P, Eichmann TO, Kraljević Pavelić S, Sedić M. The Sphingosine Kinase 2 Inhibitor ABC294640 Restores the Sensitivity of BRAFV600E Mutant Colon Cancer Cells to Vemurafenib by Reducing AKT-Mediated Expression of Nucleophosmin and Translationally-Controlled Tumour Protein. Int J Mol Sci 2021; 22:ijms221910767. [PMID: 34639107 PMCID: PMC8509245 DOI: 10.3390/ijms221910767] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/26/2021] [Accepted: 10/02/2021] [Indexed: 01/21/2023] Open
Abstract
Vemurafenib (PLX4032), small-molecule inhibitor of mutated BRAFV600E protein, has emerged as a potent anti-cancer agent against metastatic melanoma harboring BRAFV600E mutation. Unfortunately, the effect of PLX4032 in the treatment of metastatic BRAF mutated colorectal cancer (CRC) is less potent due to high incidence of fast-developing chemoresistance. It has been demonstrated that sphingolipids are important mediators of chemoresistance to various therapies in colon cancer. In this study, we will explore the role of major regulators of sphingolipid metabolism and signaling in the development of resistance to vemurafenib in BRAF mutant colon cancer cells. The obtained data revealed significantly increased expression levels of activated sphingosine kinases (SphK1 and SphK2) in resistant cells concomitant with increased abundance of sphingosine-1-phosphate (S1P) and its precursor sphingosine, which was accompanied by increased expression levels of the enzymes regulating the ceramide salvage pathway, namely ceramide synthases 2 and 6 and acid ceramidase, especially after the exposure to vemurafenib. Pharmacological inhibition of SphK1/SphK2 activities or modulation of ceramide metabolism by exogenous C6-ceramide enhanced the anti-proliferative effect of PLX4032 in resistant RKO cells in a synergistic manner. It is important to note that the inhibition of SphK2 by ABC294640 proved effective at restoring the sensitivity of resistant cells to vemurafenib at the largest number of combinations of sub-toxic drug concentrations with minimal cytotoxicity. Furthermore, the obtained findings revealed that enhanced anti-proliferative, anti-migratory, anti-clonogenic and pro-apoptotic effects of a combination treatment with ABC294640 and PLX4032 relative to either drug alone were accompanied by the inhibition of S1P-regulated AKT activity and concomitant abrogation of AKT-mediated cellular levels of nucleophosmin and translationally-controlled tumour protein. Collectively, our study suggests the possibility of using the combination of ABC294640 and PLX4032 as a novel therapeutic approach to combat vemurafenib resistance in BRAF mutant colon cancer, which warrants additional preclinical validation studies.
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Affiliation(s)
- Petra Grbčić
- Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia;
| | - Thomas O. Eichmann
- Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/III, 8010 Graz, Austria;
| | | | - Mirela Sedić
- Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, Croatia
- Correspondence: ; Tel.: +385-1-5535-135
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22
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Bai Y, Kim JY, Bisunke B, Jayne LA, Silvaroli JA, Balzer MS, Gandhi M, Huang KM, Sander V, Prosek J, Cianciolo RE, Baker SD, Sparreboom A, Jhaveri KD, Susztak K, Bajwa A, Pabla NS. Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition. Kidney Int 2021; 100:1214-1226. [PMID: 34534550 DOI: 10.1016/j.kint.2021.08.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 07/21/2021] [Accepted: 08/13/2021] [Indexed: 12/29/2022]
Abstract
A multitude of disease and therapy related factors drive the frequent development of kidney disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause kidney dysfunction through on and off-target mechanisms. Interestingly, among the small molecule inhibitors approved for the treatment of cancers that harbor BRAF-kinase activating mutations, vemurafenib can trigger tubular damage and acute kidney injury. BRAF is a proto-oncogene involved in cell growth. To investigate the underlying mechanisms, we developed cell culture and mouse models of vemurafenib kidney toxicity. At clinically relevant concentrations vemurafenib induces cell-death in transformed and primary mouse and human kidney tubular epithelial cells. In mice, two weeks of daily vemurafenib treatment causes moderate acute kidney injury with histopathological characteristics of kidney tubular epithelial cells injury. Importantly, kidney tubular epithelial cell-specific BRAF gene deletion did not influence kidney function under normal conditions or alter the severity of vemurafenib-associated kidney impairment. Instead, we found that inhibition of ferrochelatase, an enzyme involved in heme biosynthesis contributes to vemurafenib kidney toxicity. Ferrochelatase overexpression protected kidney tubular epithelial cells and conversely ferrochelatase knockdown increased the sensitivity to vemurafenib-induced kidney toxicity. Thus, our studies suggest that vemurafenib-associated kidney tubular epithelial cell dysfunction and kidney toxicity is BRAF-independent and caused, in part, by off-target ferrochelatase inhibition.
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Affiliation(s)
- Yuntao Bai
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Ji Young Kim
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Bijay Bisunke
- Department of Genetics, Genomics, and Informatics, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Laura A Jayne
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Josie A Silvaroli
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Michael S Balzer
- Department of Medicine and Genetics, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Megha Gandhi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Kevin M Huang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Veronika Sander
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Jason Prosek
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Rachel E Cianciolo
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Sharyn D Baker
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Kenar D Jhaveri
- Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra-Northwell, Northwell Health, Great Neck, New York, USA
| | - Katalin Susztak
- Department of Medicine and Genetics, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Amandeep Bajwa
- Department of Genetics, Genomics, and Informatics, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA; Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA; Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Navjot Singh Pabla
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
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23
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Rio-Vilariño A, del Puerto-Nevado L, García-Foncillas J, Cebrián A. Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance. Cancers (Basel) 2021; 13:3757. [PMID: 34359657 PMCID: PMC8345156 DOI: 10.3390/cancers13153757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer remains among the cancers with the highest incidence, prevalence, and mortality worldwide. Although the development of targeted therapies against the EGFR and VEGFR membrane receptors has considerably improved survival in these patients, the appearance of resistance means that their success is still limited. Overactivation of several members of the Ras-GTPase family is one of the main actors in both tumour progression and the lack of response to cytotoxic and targeted therapies. This fact has led many resources to be devoted over the last decades to the development of targeted therapies against these proteins. However, they have not been as successful as expected in their move to the clinic so far. In this review, we will analyse the role of these Ras-GTPases in the emergence and development of colorectal cancer and their relationship with resistance to targeted therapies, as well as the status and new advances in the design of targeted therapies against these proteins and their possible clinical implications.
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Affiliation(s)
| | | | - Jesús García-Foncillas
- Translational Oncology Division, Hospital Universitario Fundación Jimenez Diaz, 28040 Madrid, Spain; (A.R.-V.); (L.d.P.-N.)
| | - Arancha Cebrián
- Translational Oncology Division, Hospital Universitario Fundación Jimenez Diaz, 28040 Madrid, Spain; (A.R.-V.); (L.d.P.-N.)
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24
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Lassen UN, Makaroff LE, Stenzinger A, Italiano A, Vassal G, Garcia-Foncillas J, Avouac B. Precision oncology: a clinical and patient perspective. Future Oncol 2021; 17:3995-4009. [PMID: 34278817 DOI: 10.2217/fon-2021-0688] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Molecular characterization of tumors has shifted cancer treatment strategies away from nonspecific cytotoxic treatment of histology-specific tumors toward targeting of actionable mutations that can be found across multiple cancer types. The development of high-throughput technologies such as next-generation sequencing, combined with decision support applications and availability of patient databases, has provided tools that optimize disease management. Precision oncology has proven success in improving outcomes and quality of life, as well as identifying and overcoming mechanisms of drug resistance and relapse. Addressing challenges that impede its use will improve matching of therapies to patients. Here we review the current status of precision oncology medicine, emphasizing its impact on patients - what they understand about precision oncology medicine and their hopes for the future.
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Affiliation(s)
| | - Lydia E Makaroff
- Fight Bladder Cancer, Oxfordshire, OX39 4DJ, UK.,World Bladder Cancer Patient Coalition, Brussels, Belgium
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | | | - Gilles Vassal
- Gustave Roussy Comprehensive Cancer Center, & Unversity Paris-Saclay, Villejuif, 94805, France
| | - Jesus Garcia-Foncillas
- University Cancer Institute & The Department of Oncology, University Hospital Fundacion Jimenez Diaz, Autonomous University, Madrid, 28033, Spain
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25
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Abstract
B-type Raf kinase (BRAF) mutations occur in approximately 10% of patients with metastatic colorectal cancers (mCRC). Tumors harboring this mutation have a unique molecular profile and clinical phenotype. Response rate to systemic chemotherapy is poor and associated with shorter survival rate. Although BRAF inhibition dramatically changed treatment for melanoma patients, similar clinical responses were not observed in BRAF-mutant CRC, proposing a distinct mechanism of carcinogenesis. The aggressive biology of BRAF-mutated mCRC has underlined the importance of developing new therapeutic agents to improve outcomes in these patients. Despite numerous attempts, chemotherapy regimens are limited for this population. Reactivation of mitogen activated protein kinase pathway may explain the resistance to monotherapy, thus different combinations to target the pathway at different levels have been studied. This article will describe most suitable treatment options for CRC patients with BRAF mutation and discuss new emerging agents.
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26
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Kopetz S, Guthrie KA, Morris VK, Lenz HJ, Magliocco AM, Maru D, Yan Y, Lanman R, Manyam G, Hong DS, Sorokin A, Atreya CE, Diaz LA, Allegra C, Raghav KP, Wang SE, Lieu CH, McDonough SL, Philip PA, Hochster HS. Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406). J Clin Oncol 2021; 39:285-294. [PMID: 33356422 PMCID: PMC8462593 DOI: 10.1200/jco.20.01994] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/23/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
PURPOSE BRAFV600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of BRAFV600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. METHODS One hundred six patients with BRAFV600E-mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily). RESULTS Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, P = .001). The response rate was 17% versus 4% (P = .05), with a disease control rate of 65% versus 21% (P < .001). A decline in circulating tumor DNA BRAFV600E variant allele frequency was seen in 87% versus 0% of patients (P < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype. CONCLUSION Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAFV600E-mutated CRC.
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Affiliation(s)
- Scott Kopetz
- University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Van K. Morris
- University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | - Dipen Maru
- University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | | | - David S. Hong
- University of Texas MD Anderson Cancer Center, Houston, TX
| | - Alexey Sorokin
- University of Texas MD Anderson Cancer Center, Houston, TX
| | - Chloe E. Atreya
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA
| | - Luis A. Diaz
- Memorial Sloan Kettering Cancer Center, The Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD
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27
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Ruffinelli JC, Santos Vivas C, Sanz-Pamplona R, Moreno V. New advances in the clinical management of RAS and BRAF mutant colorectal cancer patients. Expert Rev Gastroenterol Hepatol 2021; 15:65-79. [PMID: 32946312 DOI: 10.1080/17474124.2021.1826305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION In colorectal carcinogenesis, genetic alterations in RAS and BRAF oncogenes play an important role for cancer initiation and/or progression and represent a key focus in the search for targeted therapies. Despite many years of research and a great amount of studies, until very recently this pathway was considered extremely hard to downregulate to obtain a significant clinical impact in colorectal cancer patients. But better times are coming with the advent of new promising drugs and combinations strategies. AREAS COVERED In this review, we go over the biological characteristics of the MAPK pathway in colorectal tumors, while illustrating the clinical correlation of RAS and BRAF mutations, particularly its prognostic and predictive value. We also present newly data about recent improvements in the treatment strategy for patients harboring these types of tumors. EXPERT COMMENTARY With great advances in the knowledge of molecular basis of RAS and BRAF mutant colorectal cancer in conjunction with biotechnology development and the constant effort for improvement, in the near future many new therapeutic options would be available for the management of this group of patient with dismal prognosis.
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Affiliation(s)
- Jose Carlos Ruffinelli
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet De Llobregat , Barcelona, Spain.,Colorectal Cancer Group, ONCOBELL Program, Institut De Recerca Biomedica De Bellvitge (IDIBELL) , Barcelona, Spain
| | - Cristina Santos Vivas
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet De Llobregat , Barcelona, Spain.,Colorectal Cancer Group, ONCOBELL Program, Institut De Recerca Biomedica De Bellvitge (IDIBELL) , Barcelona, Spain.,Consortium for Biomedical Research in Oncology (CIBERONC) , Barcelona, Spain.,Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona , Barcelona, Spain
| | - Rebeca Sanz-Pamplona
- Colorectal Cancer Group, ONCOBELL Program, Institut De Recerca Biomedica De Bellvitge (IDIBELL) , Barcelona, Spain.,Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP, Catalan Institute of Oncology (ICO), L'Hospitalet De Llobregat , Barcelona, Spain.,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) , Barcelona, Spain
| | - Victor Moreno
- Colorectal Cancer Group, ONCOBELL Program, Institut De Recerca Biomedica De Bellvitge (IDIBELL) , Barcelona, Spain.,Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona , Barcelona, Spain.,Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP, Catalan Institute of Oncology (ICO), L'Hospitalet De Llobregat , Barcelona, Spain.,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) , Barcelona, Spain
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28
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Koumaki K, Kontogianni G, Kosmidou V, Pahitsa F, Kritsi E, Zervou M, Chatziioannou A, Souliotis VL, Papadodima O, Pintzas A. BRAF paradox breakers PLX8394, PLX7904 are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 and shown by detailed pathway analysis. Biochim Biophys Acta Mol Basis Dis 2020; 1867:166061. [PMID: 33385518 DOI: 10.1016/j.bbadis.2020.166061] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/16/2020] [Accepted: 12/22/2020] [Indexed: 12/20/2022]
Abstract
PLX7904 and PLX8394 are novel BRAFV600E inhibitors-BRAFi that are designed to evade the paradoxical MAPK activation, a trait for the name "paradox breakers"-PB. Current FDA approved inhibitors (Vemurafenib, Dabrafenib, Encorafenib) although improved progression-free survival of mtBRAF melanoma patients suffer from this treatment related side effect. mtBRAF Colorectal Cancer (CRC) is resistant to the approved BRAF inhibitors, although combinatorial treatment co-targeting BRAF and EGFR/MEK is offering a promising prospect. In an effort to explore the potential of the novel BRAF inhibitors-PB to impede CRC cell proliferation, they were tested on RKO, HT29 and Colo-205 cells, bearing the BRAFV600E mutation. This study shows that the BRAF paradox breakers PLX7904 and PLX8394 cause a more prolonged MAPK pathway inhibition and achieve a stronger blockage of proliferation and reduced viability than PLX4720, the sister compound of Vemurafenib. In some treatment conditions, cells can undergo apoptosis. Genomic analysis on the more resistant RKO cells treated with PLX7904, PLX8394 and PLX4720 showed similar gene expression pattern, but the alterations imposed by the PB were more intense. Bioinformatic analysis resulted in a short list of genes representing potential master regulators of the cellular response to BRAF inhibitors' treatments. From our results, it is clear that the BRAF paradox breakers present a notable differential regulation of major pathways, like MAPK signalling, apoptosis, cell cycle, or developmental signalling pathways. Combinatorial treatments of BRAFi with Mcl-1 and Notch modulators show a better effect than mono-treatments. Additional pathways could be further exploited in novel efficient combinatorial treatment protocols with BRAFi.
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Affiliation(s)
- Kassandra Koumaki
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Georgia Kontogianni
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Vivian Kosmidou
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Fani Pahitsa
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Eftichia Kritsi
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Maria Zervou
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | | | - Vassilis L Souliotis
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Olga Papadodima
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece
| | - Alexander Pintzas
- Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
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29
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Nakayama I, Hirota T, Shinozaki E. BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation. Cancers (Basel) 2020; 12:cancers12113236. [PMID: 33152998 PMCID: PMC7694028 DOI: 10.3390/cancers12113236] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Colorectal cancer with a mutation in an oncogene BRAF has paid much attention, as it comprises a population with dismal prognosis since two decades ago. A series of research since then has successfully changed this malignancy to be treatable with specific treatment. Here we thoroughly overviewed the basic, translational and clinical studies on colorectal cancer with BRAF mutation from a physician’s viewpoint. Accumulating lines of evidence suggest that intervention of the trunk cellular growth signal transduction pathway, namely EGFR-RAS-RAF-MEK-ERK pathway, is a clue to controlling this disease. However, it is not so straightforward. Recent studies unveil the diverse and plastic nature of this signal transduction pathway. We will introduce our endeavor to conquer this condition, based on newly arriving datasets, and discuss how we could open the door to future development of CRC treatment. Abstract The Raf murine sarcoma viral oncogene homolog B (BRAF) mutation is detected in 8–12% of metastatic colorectal cancers (mCRCs) and is strongly correlated with poor prognosis. The recent success of the BEACON CRC study and the development of targeted therapy have led to the determination of BRAF-mutated mCRCs as an independent category. For nearly two decades, a growing body of evidence has established the significance of the BRAF mutation in the development of CRC. Herein, we overview both basic and clinical data relevant to BRAF-mutated CRC, mainly focusing on the development of treatment strategies. This review is organized into eight sections, including clinicopathological features, molecular features, prognosis, the predictive value of anti-epidermal growth factor receptor (EGFR) therapy, resistant mechanisms for BRAF-targeting treatment, the heterogeneity of the BRAF mutation, future perspectives, and conclusions. A characterization of the canonical mitogen-activated protein kinase (MAPK) pathway is essential for controlling this malignancy, and the optimal combination of multiple interventions for treatments remains a point of debate.
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Affiliation(s)
- Izuma Nakayama
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan
- Correspondence: (I.N.); (E.S.); Tel.: +81-3-3520-0111
| | - Toru Hirota
- Department of Experimental Pathology, Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan;
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan
- Correspondence: (I.N.); (E.S.); Tel.: +81-3-3520-0111
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30
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Kanat O, Ertas H, Caner B. Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations. World J Gastrointest Oncol 2020; 12:1080-1090. [PMID: 33133378 PMCID: PMC7579731 DOI: 10.4251/wjgo.v12.i10.1080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/07/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.
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Affiliation(s)
- Ozkan Kanat
- Department of Medical Oncology, Acıbadem Bursa Hospital, Bursa 16059, Turkey
| | - Hulya Ertas
- Department of Medical Oncology, Bursa City Hospital, Bursa 16059, Turkey
| | - Burcu Caner
- Department of Medical Oncoloy, Balıkesir Ataturk City Hospital, Bursa 16059, Turkey
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31
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The meiosis-specific cohesin component stromal antigen 3 promotes cell migration and chemotherapeutic resistance in colorectal cancer. Cancer Lett 2020; 497:112-122. [PMID: 33039558 DOI: 10.1016/j.canlet.2020.10.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/24/2020] [Accepted: 10/06/2020] [Indexed: 12/20/2022]
Abstract
Chromosome instability is one of the hallmarks of cancer. Stromal antigen (STAG) 3 is a core component of the meiosis-specific cohesin complex, which regulates sister chromatid cohesion. Although aberrantly activated genes encoding the cohesin complex have been identified in cancers, little is known about the role of STAG3 in colorectal cancer (CRC). Here, we evaluated the prognostic impact and role of STAG3 in CRC. Analysis of 172 CRC surgical specimens revealed that high STAG3 expression was associated with poor prognosis. STAG3 knockdown inhibited cell migration and increased drug sensitivity to oxaliplatin, 5-fluorouracil, irinotecan hydrochloride hydrate, and BRAF inhibitor in CRC cell lines. The enhanced drug sensitivity was also confirmed in a human organoid established from a CRC specimen. Moreover, suppression of STAG3 increased γH2AX foci. Particularly, in BRAF-mutant CRC cells, STAG3 silencing suppressed the expression of snail family transcriptional repressor 1 and phosphorylation of extracellular signal-regulated kinase via upregulation of dual-specificity phosphatase 6. Our findings suggest that STAG3 is related to poor clinical outcomes and promotes metastasis and chemotherapeutic resistance in CRC. STAG3 may be a novel prognostic marker and potential therapeutic target for CRC.
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32
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Huijberts SC, van Geel RM, Bernards R, Beijnen JH, Steeghs N. Encorafenib, binimetinib and cetuximab combined therapy for patients with BRAFV600E mutant metastatic colorectal cancer. Future Oncol 2020; 16:161-173. [PMID: 32027186 DOI: 10.2217/fon-2019-0748] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Approximately 10-15% of colorectal cancers (CRCs) harbor an activating BRAF mutation, leading to tumor growth promotion by activation of the mitogen-activated protein kinases pathway. BRAFV600E mutations are prognostic for treatment failure after first-line systemic therapy in the metastatic setting. In contrast to the efficacy of combined BRAF and MEK inhibition in melanoma, BRAFV600E mutant CRC is intrinsically unresponsive due to upregulation of HER/EGFR. However, combining the EGFR inhibitor cetuximab, the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib improves overall survival. This review discusses the current treatment field for patients with BRAFV600E mutant metastatic CRC and summarizes the pharmacology, efficacy and safety of the novel doublet and triplet therapies consisting of encorafenib and cetuximab with or without binimetinib.
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Affiliation(s)
- Sanne Cfa Huijberts
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands
| | - Robin Mjm van Geel
- Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre, Maastricht, 6229 HX, The Netherlands.,Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Rene Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.,Utrecht University, Utrecht, 3508 TC, The Netherlands
| | - Jos H Beijnen
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.,Utrecht University, Utrecht, 3508 TC, The Netherlands.,Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands
| | - Neeltje Steeghs
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.,Division of Medical Oncology, The Netherlands Cancer institute, Amsterdam, 1066 CX, The Netherlands
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33
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Owsley J, Stein MK, Porter J, In GK, Salem M, O'Day S, Elliott A, Poorman K, Gibney G, VanderWalde A. Prevalence of class I-III BRAF mutations among 114,662 cancer patients in a large genomic database. Exp Biol Med (Maywood) 2020; 246:31-39. [PMID: 33019809 DOI: 10.1177/1535370220959657] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
IMPACT STATEMENT These data represent the largest aggregation of BRAF mutations within a single clinical database to our knowledge. The relative proportions of both BRAF V600 mutations and non-V600 mutations are informative in all cancers and by malignancy, and can serve as a definitive gold-standard for BRAF mutation cancer incidence by malignancy. The rate of BRAF mutation in human cancer in a real-world large database is lower than previously reported likely representing testing more broadly across tumor types. The relative percentages of Class II and Class III BRAF mutations are higher than previously reported, representing almost 35% of BRAF mutations in cancer. These findings provide support for the development of effective treatments for non-V600 BRAF mutations in cancer.
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Affiliation(s)
- Jeff Owsley
- Division of Hematology/Oncology, University of Tennessee Health Science Center, Germantown, TN 38138, USA
| | - Matthew K Stein
- Division of Hematology/Oncology, University of Tennessee Health Science Center, Germantown, TN 38138, USA
| | | | - Gino K In
- Division of Hematology/Oncology, University of Southern California, Los Angeles, CA 90089, USA
| | | | - Steven O'Day
- John Wayne Cancer Institute, Santa Monica, CA 90404, USA
| | | | | | - Geoffrey Gibney
- Division of Hematology/Oncology, Georgetown University, Washington, DC 20007, USA
| | - Ari VanderWalde
- Division of Hematology/Oncology, University of Tennessee Health Science Center, Germantown, TN 38138, USA.,West Cancer Center, Germantown, TN 38138, USA
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Li ZN, Zhao L, Yu LF, Wei MJ. BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy. Gastroenterol Rep (Oxf) 2020; 8:192-205. [PMID: 32665851 PMCID: PMC7333923 DOI: 10.1093/gastro/goaa022] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/02/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and 30% of patients with CRC experience metastasis. Patients with metastatic colorectal cancer (mCRC) have a 5-year overall survival rate of <10%. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and V-Ki-ras2 Kirsten ratsarcoma viral oncogene homolog (KRAS) mutations are mostly studied in mCRC, as clinical trials found that first-line chemotherapy with anti-epidermal growth factor receptor agent confers limited efficacy for mCRC. Treatment decisions for early-stage mCRC do not consider BRAF or KRAS mutations, given the dramatically poor prognosis conferred by these mutations in clinical trials. Thus, it is necessary to identify patients with mCRC harboring BRAF or KRAS mutations to formulate rational therapeutic strategies to improve prognosis and survival. BRAF and KRAS mutations occur in ∼10% and ∼44% of patients with mCRC, respectively. Although the survival rate of patients with mCRC has improved in recent years, the response and prognosis of patients with the aforementioned mutations are still poor. There is a substantial unmet need for prospective personalized therapies for patients with BRAF- or KRAS-mutant mCRC. In this review, we focus on BRAF and KRAS mutations to understand the mechanisms underlying resistance and improving the response rate, outcomes, and prognosis of patients with mCRC bearing these mutations and to discuss prospective personalized therapies for BRAF- and KRAS-mutant mCRC.
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Affiliation(s)
- Zi-Nan Li
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, P. R. China.,Liaoning Engineering Technology Research Center, China Medical University, Shenyang, Liaoning, P. R. China
| | - Lin Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, P. R. China.,Liaoning Engineering Technology Research Center, China Medical University, Shenyang, Liaoning, P. R. China
| | - Li-Feng Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, P. R. China.,Liaoning Engineering Technology Research Center, China Medical University, Shenyang, Liaoning, P. R. China
| | - Min-Jie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, P. R. China.,Liaoning Engineering Technology Research Center, China Medical University, Shenyang, Liaoning, P. R. China
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35
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Assessing the translational value of pre-clinical studies for clinical response rate in oncology: an exploratory investigation of 42 FDA-approved small-molecule targeted anticancer drugs. Cancer Chemother Pharmacol 2020; 85:1015-1027. [PMID: 32424570 DOI: 10.1007/s00280-020-04076-2] [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: 01/16/2020] [Accepted: 04/24/2020] [Indexed: 10/24/2022]
Abstract
PURPOSE To assess the translational value of anticancer preclinical models, we retrospectively investigated the relationships between preclinical data and clinical response rate for 42 small-molecule targeted anticancer drugs approved by the US FDA from 2001 to 2018. METHODS For 42 FDA-approved drugs, relevant pre-clinical (IC50, mouse PK/efficacy) and clinical (overall response rates [ORR], PK) data were extracted from the public domain. Relationships were investigated overall and separately by mechanism of action and solid vs liquid tumors. Binomial-normal regression analysis was performed using R. RESULTS A significant correlation was found between the ratio of free human average plasma concentration (hCave) at the approved clinical dose to biochemical IC50 and ORR for kinase inhibitors with solid tumor indications (KIST). We also identified that, for KIST, the ratios of (i) total and (ii) free human-to-mouse average plasma concentration at efficacious doses were correlated to ORR ((i) R2 = 0.72, n = 10; (ii) R2 = 0.78, n = 10)). CONCLUSION Relationships were identified for ratios of efficacious clinical exposures to typical preclinical pharmacology data and ORR for KIST in this retrospective analysis. Although the obtained datasets are limited, the relationships demonstrate that a systemic exposure relative to established pre-clinical pharmacology experiments for an investigational KIST could be used as a reference to assess if desired efficacy could be achieved. This approach may assist selection of the recommended phase 2 dose (RP2D) of an investigational drug.
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Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther 2020; 5:22. [PMID: 32296018 PMCID: PMC7082344 DOI: 10.1038/s41392-020-0116-z] [Citation(s) in RCA: 939] [Impact Index Per Article: 187.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/24/2019] [Accepted: 12/31/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.
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Affiliation(s)
- Yuan-Hong Xie
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Ying-Xuan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
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37
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Caputo F, Santini C, Bardasi C, Cerma K, Casadei-Gardini A, Spallanzani A, Andrikou K, Cascinu S, Gelsomino F. BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights. Int J Mol Sci 2019; 20:E5369. [PMID: 31661924 PMCID: PMC6861966 DOI: 10.3390/ijms20215369] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is a heterogeneous disease, which can be classified into different subtypes, characterized by specific molecular and morphological alterations. In this context, BRAF mutations are found in about 10% of CRC patients and define a particular subtype, characterized by a dismal prognosis, with a median survival of less than 12 months. Chemotherapy plus bevacizumab is the current standard therapy in first-line treatment of BRAF-mutated metastatic CRC (mCRC), with triplet (FOLFOXIRI) plus bevacizumab as a valid option in patients with a good performance status. BRAF inhibitors are not so effective as compared to melanoma, because of various resistance mechanisms. However, the recently published results of the BEACON trial will establish a new standard of care in this setting. This review provides insights into the molecular underpinnings underlying the resistance to standard treatment of BRAF-mutated CRCs, with a focus on their molecular heterogeneity and on the research perspectives both from a translational and a clinical point of view.
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Affiliation(s)
- Francesco Caputo
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Chiara Santini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Camilla Bardasi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Krisida Cerma
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Andrea Casadei-Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Andrea Spallanzani
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Kalliopi Andrikou
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
| | - Stefano Cascinu
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
- IRCCS San Raffaele Scientific Institute Hospital, 20019 Milan, Italy.
| | - Fabio Gelsomino
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.
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38
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Jin Z, Sinicrope FA. Advances in the therapy of BRAF V600E metastatic colorectal cancer. Expert Rev Anticancer Ther 2019; 19:823-829. [PMID: 31455117 DOI: 10.1080/14737140.2019.1661778] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: BRAFV600E metastatic colorectal cancer (CRC) is an aggressive tumor subset with an approximate 8% incidence. In these patients, standard chemotherapy has limited efficacy, and the recent development of novel-targeted treatment regimens may significantly improve clinical outcome. Area covered: This review provides an overview of available data regarding advances in the first-line treatment of BRAFV600E metastatic CRC including patient tumors with microsatellite instability. The implications of BRAFV600E in earlier stage CRC are also discussed. Expert opinion: Recently, significant progress has been achieved in improving tumor response rates using a novel-targeted regimen in patients with BRAFV600E metastatic CRC. The implications of BRAFV600E in non-metastatic CRC are also becoming more evident and remains an area of ongoing investigation. The majority of CRCs with microsatellite instability high are sporadic and frequently harbor BRAFV600E. All patients with microsatellite instability high metastatic CRCs, irrespective of BRAFV600E, are candidates for immune checkpoint inhibitors. The optimal sequencing of treatment regimens for patients with BRAFV600E metastatic CRCs is an important area for future research.
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Affiliation(s)
- Zhaohui Jin
- Division of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center , Rochester , MN , USA
| | - Frank A Sinicrope
- Division of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center , Rochester , MN , USA
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39
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Thakuri PS, Gupta M, Joshi R, Singh S, Tavana H. Synergistic Inhibition of Kinase Pathways Overcomes Resistance of Colorectal Cancer Spheroids to Cyclic Targeted Therapies. ACS Pharmacol Transl Sci 2019; 2:275-284. [PMID: 32259061 DOI: 10.1021/acsptsci.9b00042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Indexed: 12/11/2022]
Abstract
Cancer cells often adapt to single-agent treatments with chemotherapeutics. Activation of alternative survival pathways is a major mechanism of drug resistance. A potential approach to block this feedback signaling is using combination treatments of a pair of drugs, although toxicity has been a limiting factor. Preclinical tumor models to identify mechanisms of drug resistance and determine low but effective combination doses are critical to effectively suppress tumor growth with reduced toxicity to patients. Using our aqueous two-phase system microtechnology, we developed colorectal tumor spheroids in high-throughput and evaluated resistance of cancer cells to three mitogen-activated protein kinase inhibitors (MAPKi) in long-term cyclic treatments. Our quantitative analysis showed that the efficacy of MAPKi significantly reduced over time, leading to an increase in proliferation of HCT116 colorectal cancer cells and growth of spheroids. We established that resistance was due to feedback activation of PI3K/AKT/mTOR pathway. Using high-throughput, dose-dependent combinations of each MAPKi and a PI3K/mTOR inhibitor, we identified low-dose, synergistic combinations that blocked resistance to MAPKi and effectively suppressed the growth of colorectal tumor spheroids in long-term treatments. Our approach to study drug resistance offers the potential to determine high priority treatments to test in animal models.
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Affiliation(s)
- Pradip Shahi Thakuri
- Department of Biomedical Engineering, The University of Akron, Akron, Ohio 44325, United States
| | - Megha Gupta
- Department of Arts and Sciences, The University of Akron, Akron, Ohio 44325, United States
| | - Ramila Joshi
- Department of Biomedical Engineering, The University of Akron, Akron, Ohio 44325, United States
| | - Sunil Singh
- Department of Biomedical Engineering, The University of Akron, Akron, Ohio 44325, United States
| | - Hossein Tavana
- Department of Biomedical Engineering, The University of Akron, Akron, Ohio 44325, United States
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40
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Cronise KE, Hernandez BG, Gustafson DL, Duval DL. Identifying the ErbB/MAPK Signaling Cascade as a Therapeutic Target in Canine Bladder Cancer. Mol Pharmacol 2019; 96:36-46. [PMID: 31048548 DOI: 10.1124/mol.119.115808] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 04/27/2019] [Indexed: 12/19/2022] Open
Abstract
Transitional cell carcinoma (TCC) of the bladder comprises 2% of diagnosed canine cancers. TCC tumors are generally inoperable and unresponsive to traditional chemotherapy, indicating a need for more effective therapies. BRAF, a kinase in the mitogen-activated protein kinase (MAPK) pathway, is mutated in 70% of canine TCCs. In this study, we use BRAF mutant and wild-type TCC cell lines to characterize the role of BRAF mutations in TCC pathogenesis and assess the efficacy of inhibition of the MAPK pathway alone and in combination with other gene targets as a treatment for canine TCC. Analysis of MAPK target gene expression and assessment of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation following serum starvation indicated constitutive MAPK activity in all TCC cell lines. BRAF mutant TCC cell lines were insensitive to the BRAF inhibitor vemurafenib, with IC50 values greater than 5 μM, but exhibited greater sensitivity to a paradox-breaking BRAF inhibitor (IC50: 0.2-1 μM). All TCC cell lines had IC50 values less than 7 nM to the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor trametinib independent of their BRAF mutation status. ERK1/2 phosphorylation decreased after 6-hour treatments with MAPK inhibitors, but rebounded by 24 hours, suggesting the presence of resistance mechanisms. Microarray analysis identified elevated expression of the ErbB family of receptors and ligands in TCC cell lines. The pan-ErbB inhibitor sapitinib synergized with BRAF inhibition in BRAF mutant Bliley TCC cells and synergized with MEK1/2 inhibition in Bliley and BRAF wild-type Kinsey cells. These findings suggest the potential for combined MAPK and ErbB receptor inhibition as a therapy for canine TCC. SIGNIFICANCE STATEMENT: The results of this study (1) identify a novel combination strategy for canine bladder cancer treatment: targeting the ErbB/MAPK signaling cascade and (2) establish the utility of canine bladder cancer as a naturally-occurring model for human MAPK-driven cancers.
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Affiliation(s)
- Kathryn E Cronise
- Flint Animal Cancer Center, Department of Clinical Sciences (K.E.C., B.G.H., D.L.G., D.L.D.), and Cell and Molecular Biology Graduate Program (K.E.C., D.L.G., D.L.D.), Colorado State University, Fort Collins, Colorado; and University of Colorado Cancer Center, Aurora, Colorado (D.L.G., D.L.D.)
| | - Belen G Hernandez
- Flint Animal Cancer Center, Department of Clinical Sciences (K.E.C., B.G.H., D.L.G., D.L.D.), and Cell and Molecular Biology Graduate Program (K.E.C., D.L.G., D.L.D.), Colorado State University, Fort Collins, Colorado; and University of Colorado Cancer Center, Aurora, Colorado (D.L.G., D.L.D.)
| | - Daniel L Gustafson
- Flint Animal Cancer Center, Department of Clinical Sciences (K.E.C., B.G.H., D.L.G., D.L.D.), and Cell and Molecular Biology Graduate Program (K.E.C., D.L.G., D.L.D.), Colorado State University, Fort Collins, Colorado; and University of Colorado Cancer Center, Aurora, Colorado (D.L.G., D.L.D.)
| | - Dawn L Duval
- Flint Animal Cancer Center, Department of Clinical Sciences (K.E.C., B.G.H., D.L.G., D.L.D.), and Cell and Molecular Biology Graduate Program (K.E.C., D.L.G., D.L.D.), Colorado State University, Fort Collins, Colorado; and University of Colorado Cancer Center, Aurora, Colorado (D.L.G., D.L.D.)
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41
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Coppé JP, Mori M, Pan B, Yau C, Wolf DM, Ruiz-Saenz A, Brunen D, Prahallad A, Cornelissen-Steijger P, Kemper K, Posch C, Wang C, Dreyer CA, Krijgsman O, Lee PRE, Chen Z, Peeper DS, Moasser MM, Bernards R, van 't Veer LJ. Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities. Nat Cell Biol 2019; 21:778-790. [PMID: 31160710 DOI: 10.1038/s41556-019-0328-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 04/09/2019] [Indexed: 12/21/2022]
Abstract
Phosphorylation networks intimately regulate mechanisms of response to therapies. Mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. Here, we introduce a practical high-throughput system to measure the enzymatic activity of kinases using biological peptide targets as phospho-sensors to reveal kinase dependencies in tumour biopsies and cell lines. A 228-peptide screen was developed to detect the activity of >60 kinases, including ABLs, AKTs, CDKs and MAPKs. Focusing on BRAFV600E tumours, we found mechanisms of intrinsic resistance to BRAFV600E-targeted therapy in colorectal cancer, including targetable parallel activation of PDPK1 and PRKCA. Furthermore, mapping the phospho-catalytic signatures of melanoma specimens identifies RPS6KB1 and PIM1 as emerging druggable vulnerabilities predictive of poor outcome in BRAFV600E patients. The results show that therapeutic resistance can be caused by the concerted upregulation of interdependent pathways. Our kinase activity-mapping system is a versatile strategy that innovates the exploration of actionable kinases for precision medicine.
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Affiliation(s)
- Jean-Philippe Coppé
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
| | - Miki Mori
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Department of Breast Surgical Oncology, Showa University, Tokyo, Japan
| | - Bo Pan
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Christina Yau
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Denise M Wolf
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Ana Ruiz-Saenz
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Diede Brunen
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Anirudh Prahallad
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | | | - Kristel Kemper
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Christian Posch
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany.,School of Medicine, Sigmund Freud University, Vienna, Austria
| | - Changjun Wang
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.,Department of Breast Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Courtney A Dreyer
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Oscar Krijgsman
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Pei Rong Evelyn Lee
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Zhongzhong Chen
- The State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,Department of Urology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Daniel S Peeper
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Mark M Moasser
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - René Bernards
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Laura J van 't Veer
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
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42
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Goulielmaki M, Assimomytis N, Rozanc J, Taki E, Christodoulou I, Alexopoulos LG, Zoumpourlis V, Pintzas A, Papahatjis D. DPS-2: A Novel Dual MEK/ERK and PI3K/AKT Pathway Inhibitor with Powerful Ex Vivo and In Vivo Anticancer Properties. Transl Oncol 2019; 12:932-950. [PMID: 31096110 PMCID: PMC6520640 DOI: 10.1016/j.tranon.2019.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 02/07/2019] [Accepted: 04/01/2019] [Indexed: 01/06/2023] Open
Abstract
Development of novel bioactive compounds against KRAS and/or BRAF mutant colorectal cancer (CRC) is currently an urgent need in oncology. In addition, single or multitarget kinase inhibitors against MEK/ERK and PI3K/AKT pathways are of potential therapeutic advantage. A new compound based on the benzothiophene nucleus was synthesized, based on previous important outcomes on other pharmaceutical preparations, to be tested as potential anticancer agent. Treatments by 2-5 μM DPS-2 of several CRC and melanoma cell lines bearing either BRAF or KRAS mutations have shown a remarkable effect on cell viability in 2D and 3D cultures. More detailed analysis has shown that DPS-2 can kill cancer cells by apoptosis, reducing at the same time their autophagy properties. After testing activities of several signaling pathways, the compound was found to have a dual inhibition of two major proliferative/survival pathways, MEK/ERK and PI3K/AKT, in both CRC and melanoma, thus providing a mechanistic evidence for its potent anticancer activity. Antitumor activity of DPS-2 was further validated in vivo, as DPS-2 treatment of mouse xenografts of Colo-205 colorectal cancer cells remarkably reduced their tumor formation properties. Our findings suggest that DPS-2 has significant anti-KRAS/ anti-BRAF mutant CRC activity in preclinical models, potentially providing a novel treatment strategy for these difficult-to-treat tumors, which needs to be further exploited.
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Affiliation(s)
- Maria Goulielmaki
- Institute of Biology Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 116 36 Athens, Greece
| | - Nikos Assimomytis
- Institute of Biology Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 116 36 Athens, Greece
| | - Jan Rozanc
- TEPA Lefkippos-Demokritos, Patriarchou Grigoriou & Neapoleos, 15343 Ag. Paraskevi, Attiki, Greece
| | - Eleni Taki
- Institute of Biology Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 116 36 Athens, Greece
| | - Ioannis Christodoulou
- Institute of Biology Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 116 36 Athens, Greece
| | - Leonidas G Alexopoulos
- TEPA Lefkippos-Demokritos, Patriarchou Grigoriou & Neapoleos, 15343 Ag. Paraskevi, Attiki, Greece; School of Mechanical Engineering, National Technical University of Athens, Zografou 15780, Greece
| | - Vassilis Zoumpourlis
- Institute of Biology Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 116 36 Athens, Greece
| | - Alexandros Pintzas
- Institute of Biology Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 116 36 Athens, Greece
| | - Demetris Papahatjis
- Institute of Biology Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 116 36 Athens, Greece.
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43
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Hao J, Fan W, Li Y, Tang R, Tian C, Yang Q, Zhu T, Diao C, Hu S, Chen M, Guo P, Long Q, Zhang C, Qin G, Yu W, Chen M, Li L, Qin L, Wang J, Zhang X, Ren Y, Zhou P, Zou L, Jiang K, Guo W, Deng W. Melatonin synergizes BRAF-targeting agent vemurafenib in melanoma treatment by inhibiting iNOS/hTERT signaling and cancer-stem cell traits. J Exp Clin Cancer Res 2019; 38:48. [PMID: 30717768 PMCID: PMC6360719 DOI: 10.1186/s13046-019-1036-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 01/13/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND As the selective inhibitor of BRAF kinase, vemurafenib exhibits effective antitumor activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after its initial treatment. METHODS Immunohistochemical staining was performed to detect the expression of iNOS and hTERT, p-p65, Epcam, CD44, PCNA in mice with melanoma xenografts. The proliferation and migration of melanoma cells were detected by MTT, tumorsphere culture, cell cycle, cell apoptosis, AO/EB assay and colony formation, transwell assay and scratch assay in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the iNOS/hTERT signaling pathways were detected by western blot. Nucleus-cytoplasm separation, and immunofluorescence analyses were conducted to explore the location of p50/p65 in melanoma cell lines. Flow cytometry assay were performed to determine the expression of CD44. Pull down assay and ChIP assay were performed to detect the binding ability of p65 at iNOS and hTERT promoters. Additionally, hTERT promoter-driven luciferase plasmids were transfected in to melanoma cells with indicated treatment to determine luciferase activity of hTERT. RESULTS Melatonin significantly and synergistically enhanced vemurafenib-mediated inhibitions of proliferation, colony formation, migration and invasion and promoted vemurafenib-induced apoptosis, cell cycle arresting and stemness weakening in melanoma cells. Further mechanism study revealed that melatonin enhanced the antitumor effect of vemurafenib by abrogating nucleus translocation of NF-κB p50/p65 and their binding at iNOS and hTERT promoters, thereby suppressing the expression of iNOS and hTERT. The elevated anti-tumor capacity of vemurafenib upon co-treatment with melatonin was also evaluated and confirmed in mice with melanoma xenografts. CONCLUSIONS Collectively, our results demonstrate melatonin synergizes the antitumor effect of vemurafenib in human melanoma by inhibiting cell proliferation and cancer-stem cell traits via targeting NF-κB/iNOS/hTERT signaling pathway, and suggest the potential of melatonin in antagonizing the toxicity of vemurafenib and augmenting its sensitivities in melanoma treatment.
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Affiliation(s)
- Jiaojiao Hao
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Wenhua Fan
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Yizhuo Li
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Ranran Tang
- Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, China
| | - Chunfang Tian
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Qian Yang
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Tianhua Zhu
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Chaoliang Diao
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Sheng Hu
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Manyu Chen
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Ping Guo
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Qian Long
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Changlin Zhang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Ge Qin
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Wendan Yu
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Miao Chen
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Liren Li
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Lijun Qin
- Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingshu Wang
- Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | | | | | - Penghui Zhou
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Lijuan Zou
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Kui Jiang
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Wei Guo
- Institute of Cancer Stem Cells and The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Wuguo Deng
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China
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44
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Induced cross-resistance of BRAF V600E melanoma cells to standard chemotherapeutic dacarbazine after chronic PLX4032 treatment. Sci Rep 2019; 9:30. [PMID: 30631106 PMCID: PMC6328535 DOI: 10.1038/s41598-018-37188-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 11/28/2018] [Indexed: 12/16/2022] Open
Abstract
The maximum response and 10-year survival rate for metastatic melanoma patients treated with standardised chemotherapy is still less than 15% and 10%, respectively. In contrast, oncogene targeting was found a promising tool for killing of BRAFV600 mutated melanoma cells. Nevertheless, despite improved response and survival rates, resistance acquisition remains an ongoing problem. In this context, the impact of chronic BRAF inhibition on the efficacy of commonly applied cytostatics is still unknown. In our study, human melanoma cells with BRAFV600E mutation were treated with chemotherapeutics and a BRAF inhibitor. Resistance patterns were analysed by microelectrode array-based impedance spectroscopy, XTT and flow cytometric apoptosis/proliferation assay. BRAFV600E melanoma cells acquired a time- and concentration-dependent desensitisation up to 100-fold towards oncogene-specific PLX4032 and chemotherapeutic dacarbazine after twelve months treatment. The impact of multiple drug insensitivity on molecular melanoma characteristics was elaborated via mRNA and protein quantification. Following BRAFV600E targeting, melanoma cells developed an increasingly aggressive, dacarbazine-insensitive phenotype. Thereby, hyperactivated canonical alternative MAPK and bypass PI3K/AKT signalling caused cross-resistance of differently acting drugs. With these results, we are the first to show that long-term melanoma therapy with BRAF inhibitors can prevent further therapeutic success with dacarbazine due to acquisition of cross-resistance.
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45
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Shahi Thakuri P, Luker GD, Tavana H. Cyclical Treatment of Colorectal Tumor Spheroids Induces Resistance to MEK Inhibitors. Transl Oncol 2018; 12:404-416. [PMID: 30550927 PMCID: PMC6299152 DOI: 10.1016/j.tranon.2018.11.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/19/2018] [Accepted: 11/19/2018] [Indexed: 12/18/2022] Open
Abstract
Adaptive drug resistance is a major obstacle to successful treatment of colorectal cancers. Physiologic tumor models of drug resistance are crucial to understand mechanisms of treatment failure and improve therapy by developing new therapeutics and treatment strategies. Using our aqueous two-phase system microtechnology, we developed colorectal tumor spheroids and periodically treated them with sub-lethal concentrations of three Mitogen Activated Kinase inhibitors (MEKi) used in clinical trials. We used long-term, periodic treatment and recovery of spheroids to mimic cycles of clinical chemotherapy and implemented a growth rate metric to quantitatively assess efficacy of the MEKi during treatment. Our results showed that efficacy of the MEKi significantly reduced with increased treatment cycles. Using a comprehensive molecular analysis, we established that resistance of colorectal tumor spheroids to the MEKi developed through activation of the PI3K/AKT/mTOR pathway. We also showed that other potential feedback mechanisms, such as STAT3 activation or amplified B-RAF, did not account for resistance to the MEKi. We combined each of the three MEKi with a PI3K/mTOR inhibitor and showed that the combination treatments synergistically blocked resistance to the MEKi. Importantly, and unlike the individual inhibitors, we demonstrated that synergistic concentrations of combinations of MEK and PI3K/mTOR inhibitors effectively inhibited growth of colorectal tumor spheroids in long-term treatments. This proof-of-concept study to model treatment-induced drug resistance of cancer cells using 3D cultures offers a unique approach to identify underlying molecular mechanisms and develop effective treatments.
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Affiliation(s)
- Pradip Shahi Thakuri
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA
| | - Gary D Luker
- Department of Radiology, University of Michigan, Ann Arbor, MI 48105, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48105, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48105, USA
| | - Hossein Tavana
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA.
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46
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Yanagihara K, Kubo T, Mihara K, Kuwata T, Ochiai A, Seyama T, Yokozaki H. Establishment of a novel cell line from a rare human duodenal poorly differentiated neuroendocrine carcinoma. Oncotarget 2018; 9:36503-36514. [PMID: 30559933 PMCID: PMC6284856 DOI: 10.18632/oncotarget.26367] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/01/2018] [Indexed: 12/17/2022] Open
Abstract
Poorly differentiated neuroendocrine carcinoma of the duodenum (D-NEC) is a rare cancer with poor prognosis. However, a D-NEC cell line has not yet been established to study the disease. We established a cell line, TCC-NECT-2, from the ascites tumor of a 59-year-old male Japanese patient with D-NEC. TCC-NECT-2 was positive for neuroendocrine markers, chromogranin A (CGA), cluster of differentiation 56 (CD56/NCAM), synaptophysin (SYN/p38), and neuron specific enolase (NSE). Cells exhibited retinoblastoma (RB) protein loss. Orthotopic implantation of TCC-NECT-2 cells into nu/nu mice resulted in tumor formation (incidence = 83.3%) with neuroendocrine characteristics, metastasis, and weight loss. BRAFV600E and TP53 mutations and C-MYC gene amplification were also observed in TCC-NECT-2. BRAFV600E-expressing TCC-NECT-2 cells were sensitive to BRAF inhibitor vemurafenib, and especially dabrafenib, in vitro, and were strongly inhibited in a dose-dependent manner. Dabrafenib treatment (30 mg/kg) in a xenograft model for 14 days significantly suppressed tumor growth (percent tumor growth inhibition, TGI% = 48.04). An enhanced therapeutic effect (TGI% = 95.81) was observed on combined treatment of dabrafenib and irinotecan (40 mg/kg). Therefore, TCC-NECT-2, the first reported cell line derived from D-NEC, might serve as a useful model to study the basic biology of D-NEC and translational applications for treatment.
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Affiliation(s)
- Kazuyoshi Yanagihara
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan.,Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takanori Kubo
- Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Hiroshima, Japan
| | - Keichiro Mihara
- Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan
| | - Atsushi Ochiai
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Toshio Seyama
- Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Hiroshima, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
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47
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Wang K, Li Y, Song N, Che X, Hou K, Xu L, Bai M, Wang Q, Wang Y, Zhou Y, Cao M, Liu Y, Zhang J. Signal transducer and activator of transcription 3 inhibition enhances vemurafenib sensitivity in colon cancers harboring the BRAF V600E mutation. J Cell Biochem 2018; 120:5315-5325. [PMID: 30320916 DOI: 10.1002/jcb.27808] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 09/12/2018] [Indexed: 01/05/2023]
Abstract
The BRAFV600E inhibitor vemurafenib is widely used to treat melanomas harboring the activated BRAFV600E mutation; however, vemurafenib showed poor efficacy in colon cancer, which impeded its clinical application for colon cancer patients with this mutation. The specific mechanism of vemurafenib resistance is not clear in colon cancer. In this study, we demonstrated that signal transducer and activator of transcription 3 (STAT3) activation influenced vemurafenib sensitivity in BRAFV600E mutant colon cancer cells. When vemurafenib was applied to two colon cancer cell lines with the BRAFV600E mutation, STAT3 was continuously activated after 6 hours. Furthermore, BCL-2 was upregulated in RKO colon cancer cells, while STAT3 remained unchanged in HT-29 colon cancer cells. This suggested that STAT3 signaling might be involved in vemurafenib sensitivity. Combining the STAT3 inhibitor STATTIC with vemurafenib further inhibited cell proliferation and promoted apoptosis by downregulating STAT3 and BCL-2 expression in RKO cells. Further studies showed that interleukin 6 (IL-6) secretion increased after RKO cells were treated with vemurafenib. STAT3 activation was induced by adding IL-6 to the supernatant, and IL-6 increased STAT3 and BCL-2 expression and antagonized vemurafenib sensitivity in HT-29 cells. Together, these results suggest that STAT3 activation maybe related to vemurafenib sensitivity in colon cancer cells, and that combining STAT3 inhibitors with vemurafenib may be a promising treatment for BRAFV600E mutant colon cancers.
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Affiliation(s)
- Kai Wang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Yanrong Li
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Na Song
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Kezuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Ling Xu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Ming Bai
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Qiwei Wang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Yuanhe Wang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Yang Zhou
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Meihui Cao
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Jingdong Zhang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
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48
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Pan JH, Zhou H, Zhu SB, Huang JL, Zhao XX, Ding H, Pan YL. Development of small-molecule therapeutics and strategies for targeting RAF kinase in BRAF-mutant colorectal cancer. Cancer Manag Res 2018; 10:2289-2301. [PMID: 30122982 PMCID: PMC6078078 DOI: 10.2147/cmar.s170105] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
RAF kinase is crucially involved in cell proliferation and survival in colorectal cancer (CRC). Patients with metastatic CRC (mCRC) harboring BRAF mutations (BRAFms) not only experience a poor prognosis but also benefit less from therapeutics targeting ERK signaling. With advances in RAF inhibitors and second-generation inhibitors including encorafenib and vemurafenib, which have been approved for treating BRAF-V600E malignancies, the combinatorial therapeutic strategies of RAF inhibitors elicit remarkable responses in patients with BRAF-V600E mCRC. However, the therapeutic efficacy is restricted by resistance, which might be due to RAF dimerization and reactivation of the MAPK pathway. In addition, the next-generation RAF inhibitors, which are characterized by varying structural and biochemical properties, have achieved preclinical and clinical advances. Herein, we summarize the existing mechanism of RAF kinases in CRC, including MAPK feedback reactivation of resistance to RAF inhibitors. We additionally summarize the development of three generations of RAF inhibitors and different therapeutic strategies including the combination of EGFR, BRAF, and PI3K inhibitors for BRAFm CRC treatment.
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Affiliation(s)
- Jing-Hua Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China,
| | - Hong Zhou
- Department of Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Sheng-Bin Zhu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China,
| | - Jin-Lian Huang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China,
| | - Xiao-Xu Zhao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China,
| | - Hui Ding
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China,
| | - Yun-Long Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China,
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49
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Lou E. The Art of War and oncology: applying the principles of strategy and tactics to greater effect in the era of targeted therapy. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:168. [PMID: 29911116 DOI: 10.21037/atm.2018.03.04] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Emil Lou
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, MN, USA
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50
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Xu Y, Müller P, Tsimberidou AM, Berry D. A nonparametric Bayesian basket trial design. Biom J 2018; 61:1160-1174. [PMID: 29808479 DOI: 10.1002/bimj.201700162] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 04/09/2018] [Accepted: 04/13/2018] [Indexed: 12/13/2022]
Abstract
Targeted therapies on the basis of genomic aberrations analysis of the tumor have shown promising results in cancer prognosis and treatment. Regardless of tumor type, trials that match patients to targeted therapies for their particular genomic aberrations have become a mainstream direction of therapeutic management of patients with cancer. Therefore, finding the subpopulation of patients who can most benefit from an aberration-specific targeted therapy across multiple cancer types is important. We propose an adaptive Bayesian clinical trial design for patient allocation and subpopulation identification. We start with a decision theoretic approach, including a utility function and a probability model across all possible subpopulation models. The main features of the proposed design and population finding methods are the use of a flexible nonparametric Bayesian survival regression based on a random covariate-dependent partition of patients, and decisions based on a flexible utility function that reflects the requirement of the clinicians appropriately and realistically, and the adaptive allocation of patients to their superior treatments. Through extensive simulation studies, the new method is demonstrated to achieve desirable operating characteristics and compares favorably against the alternatives.
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Affiliation(s)
- Yanxun Xu
- Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, 21218, USA
| | - Peter Müller
- Department of Mathematics, University of Texas at Austin, Austin, TX, 78705, USA
| | - Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77005, USA
| | - Donald Berry
- Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77005, USA
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