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Rota M, Sganzerla F, Zuffante M, Mafficini A, Pavarana M, Milella M. Case report: Male genital system, soft tissue and myocardial metastases in a patient with exon 11-mutated GIST of unknown origin. Front Oncol 2024; 14:1450889. [PMID: 39290240 PMCID: PMC11405151 DOI: 10.3389/fonc.2024.1450889] [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: 06/18/2024] [Accepted: 08/22/2024] [Indexed: 09/19/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract, usually arising in the stomach or in the small bowel. Most GISTs are diagnosed early due to the presence of symptoms (e.g., abdominal discomfort/pain, anemia, etc.); at times, diagnosis could be incidental (e.g., ultrasound or endoscopic examinations performed for other reasons, surgical intervention for a different disease, etc.). Diagnosis occurs when the tumor is already metastatic in 10-20% of cases. The most common metastatic sites are liver, peritoneum, and loco-regional lymph nodes. Here, we present the case of a male patient with an atypical presentation of disease: as a matter of fact, during his oncological history, he developed metastases in unlikely sites, such as penis, scrotum, myocardium, and soft tissues.
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Affiliation(s)
- Michele Rota
- Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine, University of Verona and Verona University and Hospital Trust, Verona, Italy
| | - Federico Sganzerla
- Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine, University of Verona and Verona University and Hospital Trust, Verona, Italy
| | - Michele Zuffante
- Nuclear Medicine Unit, Integrated University Hospital of Verona, Verona, Italy
| | - Andrea Mafficini
- Department of Engineering for Innovation Medicine, University of Verona and Verona University and Hospital Trust, Verona, Italy
- Applied Research on Cancer (ARC)-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy
| | - Michele Pavarana
- Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine, University of Verona and Verona University and Hospital Trust, Verona, Italy
| | - Michele Milella
- Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine, University of Verona and Verona University and Hospital Trust, Verona, Italy
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2
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Farhat F, Hussein M, Sbaity E, Alsharm A, Rasul K, Khairallah S, Assi T, Allahverdi N, Othman A, Kattan J. Gastrointestinal stromal tumor in North Africa and the middle east: updates in presentation and management from an 11-year retrospective cohort. Hosp Pract (1995) 2023; 51:275-287. [PMID: 38112178 DOI: 10.1080/21548331.2023.2277682] [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: 02/07/2023] [Accepted: 10/25/2023] [Indexed: 12/21/2023]
Abstract
OBJECTIVES This study described the epidemiological, clinical, and survival profiles of patients with gastrointestinal stromal tumor (GIST) in North Africa and the Middle East (AfME). METHODS This regional, multicenter, observational, retrospective study collected 11-year data on demographics, medical history, disease characteristics, current treatment approaches of GIST, the safety of the most common tyrosine kinase inhibitors (TKIs), second cancers, and survival status. RESULTS Data of 201 eligible patients were analyzed: mean age was 56.9 ± 12.6 years; 111 (55.2%) patients were men, 21 (10.4%) patients had previous personal malignancy. The most common clinical presentation of GIST was dysphagia [92 (45.8%) patients]. The stomach was the most common primary site in 120 (60.7%) patients, 171 (85.1%) patients had localized disease at diagnosis. 198 (98.5%) GIST cases were CD117/CD34-positive. Imatinib was used in the neoadjuvant (18/21 patients), adjuvant (85/89 patients), and first-line metastatic treatment (28/33 patients) settings. The most common non-hematological toxicity associated with TKIs was vomiting in 32/85 (37.6%) patients. Overall, 100 (49.8%) patients (95%CI: 42.8-56.7%) were alive and disease-free while 30 (14.9%) patients were alive with active disease. CONCLUSION Presentation of GIST in our AfME population is consistent with global reports, being more frequent in patients >50 years old and having the stomach as the most common primary site. Unlike what is usually reported, though, we did have more patients with lymphatic spread of the disease. Despite the global trend and advances in the treatment of GIST according to molecular profile, this is still far to happen in our population given the lack of access to molecular profiles and the high associated cost.
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Affiliation(s)
- Fadi Farhat
- Department of Onco-Hematology, Mount Lebanon Hospital University Medical Center, Balamand University, Beirut, Hazmieh, Lebanon
| | - Marwa Hussein
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Eman Sbaity
- Department of General Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Abdullah Alsharm
- Oncology Department, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Kakil Rasul
- Department of Hematology-Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | | | - Tarek Assi
- Department of Onco-Hematology, Mount Lebanon Hospital University Medical Center, Balamand University, Beirut, Hazmieh, Lebanon
- Department of Hematology-Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Niloofar Allahverdi
- Translational Cancer Research Facility and Clinical Trial Unit, Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Ahmad Othman
- Department of Hematology-Oncology, Hammoud Hospital University Medical Center, Saida, Lebanon
| | - Joseph Kattan
- Department of Hematology-Oncology, Hôtel-Dieu de France University Hospital, Beirut, Lebanon
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Rönnberg H. Signal Transduction Inhibitors. THERAPEUTIC STRATEGIES IN VETERINARY ONCOLOGY 2023:89-110. [DOI: 10.1079/9781789245820.0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Su R, Li C, Wang X, Li Z, Wen Z, Yin Z, Huang G, Liu Y, Yang J, Hu H, Nie H, Zhang K, Fei J. PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 32:729-742. [PMID: 37234746 PMCID: PMC10208829 DOI: 10.1016/j.omtn.2023.04.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/28/2023] [Indexed: 05/28/2023]
Abstract
A large proportion of patients with chronic myeloid leukemia (CML; 20%-50%) develop resistance to imatinib in a BCR-ABL1-independent manner. Therefore, new therapeutic strategies for use in this subset of imatinib-resistant CML patients are urgently needed. In this study, we used a multi-omics approach to show that PPFIA1 was targeted by miR-181a. We demonstrate that both miR-181a and PPFIA1-siRNA reduced the cell viability and proliferative capacity of CML cells in vitro, as well as prolonged the survival of B-NDG mice harboring human BCR-ABL1-independent imatinib-resistant CML cells. Furthermore, treatment with miR-181a mimic and PPFIA1-siRNA inhibited the self-renewal of c-kit+ and CD34+ leukemic stem cells and promoted their apoptosis. Small activating (sa)RNAs targeting the promoter of miR-181a increased the expression of endogenous primitive miR-181a (pri-miR-181a). Transfection with saRNA 1-3 inhibited the proliferation of imatinib-sensitive and -resistant CML cells. However, only saRNA-3 showed a stronger and more sustained inhibitory effect than the miR-181a mimic. Collectively, these results show that miR-181a and PPFIA1-siRNA may overcome the imatinib resistance of BCR-ABL1-independent CML, partially by inhibiting the self-renewal of leukemia stem cells and promoting their apoptosis. Moreover, exogenous saRNAs represent promising therapeutic agents in the treatment of imatinib-resistant BCR-ABL1-independent CML.
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Affiliation(s)
- Rui Su
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Chuting Li
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Xiuyuan Wang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Zhendong Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, Guangdong, China
| | - Ziqi Wen
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Zhao Yin
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Guiping Huang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Yanjun Liu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Juhua Yang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Haiyan Hu
- Clinical Trial Center of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- Oncology Department of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Hong Nie
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Keda Zhang
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China
| | - Jia Fei
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
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Mlejnek P. What Is the Significance of Lysosomal-Mediated Resistance to Imatinib? Cells 2023; 12:cells12050709. [PMID: 36899844 PMCID: PMC10000661 DOI: 10.3390/cells12050709] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/16/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
The lysosomal sequestration of hydrophobic weak-base anticancer drugs is one proposed mechanism for the reduced availability of these drugs at target sites, resulting in a marked decrease in cytotoxicity and consequent resistance. While this subject is receiving increasing emphasis, it is so far only in laboratory experiments. Imatinib is a targeted anticancer drug used to treat chronic myeloid leukaemia (CML), gastrointestinal stromal tumours (GISTs), and a number of other malignancies. Its physicochemical properties make it a typical hydrophobic weak-base drug that accumulates in the lysosomes of tumour cells. Further laboratory studies suggest that this might significantly reduce its antitumor efficacy. However, a detailed analysis of published laboratory studies shows that lysosomal accumulation cannot be considered a clearly proven mechanism of resistance to imatinib. Second, more than 20 years of clinical experience with imatinib has revealed a number of resistance mechanisms, none of which is related to its accumulation in lysosomes. This review focuses on the analysis of salient evidence and raises a fundamental question about the significance of lysosomal sequestration of weak-base drugs in general as a possible resistance mechanism both in clinical and laboratory settings.
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Affiliation(s)
- Petr Mlejnek
- Department of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, 77515 Olomouc, Czech Republic
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Muacevic A, Adler JR, Zeng J, Collins V, Zeizafoun N. A Rare Case of Breast Metastatic Gastrointestinal Stromal Tumor. Cureus 2023; 15:e34164. [PMID: 36843793 PMCID: PMC9949736 DOI: 10.7759/cureus.34164] [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] [Accepted: 01/22/2023] [Indexed: 01/25/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is one of the most common spindle cell neoplasms of the alimentary system, and can arise anywhere along the gastrointestinal tract (GI). Its incidence rate is up to 22 cases per million, with a minor geographic variation. GIST is thought to originate from interstitial cell of Cajal, and its pathogenesis is related to molecular defects, such as KIT receptor tyrosine kinase or platelet-derived growth receptor alpha gene activation. While the majority of GISTs are known to show a benign disease course, metastases of high-grade forms to different organ systems have been seldom reported. We present a case with an unprecedented metastasis of GIST to the breast. The patient is a 62-year-old female with a history of the primary resection of GIST from the small intestine. Her disease course was initially complicated by multiple metastases, solely localized to the liver for which she had a living-donor liver transplant. The tumor harbored both KIT exon 11 and exon 17 mutation. Fourteen months post-transplant, the patient was found to have metastatic GIST on her breast biopsy. GIST metastasis to the breast is extremely rare. A consideration of this spindle cell neoplasm as a differential is recommended when clinical suspicion arises. The pathophysiology, current diagnostic tool, grading system, and treatment of this tumor are discussed.
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7
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Hu X, Wang Z, Su P, Zhang Q, Kou Y. Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors. Front Oncol 2022; 12:933248. [PMID: 36147927 PMCID: PMC9485670 DOI: 10.3389/fonc.2022.933248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 08/18/2022] [Indexed: 11/15/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At present, surgery is the first-line treatment for primary resectable GISTs; however, the recurrence rate is high. Imatinib mesylate (IM) is an effective first-line drug used for the treatment of unresectable or metastatic recurrent GISTs. More than 80% of patients with GISTs show significantly improved 5-year survival after treatment; however, approximately 50% of patients develop drug resistance after 2 years of IM treatment. Therefore, an in-depth research is urgently needed to reveal the mechanisms of secondary resistance to IM in patients with GISTs and to develop new therapeutic targets and regimens to improve their long-term prognoses. In this review, research on the mechanisms of secondary resistance to IM conducted in the last 5 years is discussed and summarized from the aspects of abnormal energy metabolism, gene mutations, non-coding RNA, and key proteins. Studies have shown that different drug-resistance mechanism networks are closely linked and interconnected. However, the influence of these drug-resistance mechanisms has not been compared. The combined inhibition of drug-resistance mechanisms with IM therapy and the combined inhibition of multiple drug-resistance mechanisms are expected to become new therapeutic options in the treatment of GISTs. In addition, implementing individualized therapies based on the identification of resistance mechanisms will provide new adjuvant treatment options for patients with IM-resistant GISTs, thereby delaying the progression of GISTs. Previous studies provide theoretical support for solving the problems of drug-resistance mechanisms. However, most studies on drug-resistance mechanisms are still in the research stage. Further clinical studies are needed to confirm the safety and efficacy of the inhibition of drug-resistance mechanisms as a potential therapeutic target.
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Affiliation(s)
- Xiangchen Hu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Peng Su
- Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qiqi Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Youwei Kou
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Youwei Kou,
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8
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Li J, Guo S, Sun Z, Fu Y. Noncoding RNAs in Drug Resistance of Gastrointestinal Stromal Tumor. Front Cell Dev Biol 2022; 10:808591. [PMID: 35174150 PMCID: PMC8841737 DOI: 10.3389/fcell.2022.808591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/10/2022] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tracts and a model for the targeted therapy of solid tumors because of the oncogenic driver mutations in KIT and PDGDRA genes, which could be effectively inhibited by the very first targeted agent, imatinib mesylate. Most of the GIST patients could benefit a lot from the targeted treatment of this receptor tyrosine kinase inhibitor. However, more than 50% of the patients developed resistance within 2 years after imatinib administration, limiting the long-term effect of imatinib. Noncoding RNAs (ncRNAs), the non-protein coding transcripts of human, were demonstrated to play pivotal roles in the resistance of various chemotherapy drugs. In this review, we summarized the mechanisms of how ncRNAs functioning on the drug resistance in GIST. During the drug resistance of GIST, there were five regulating mechanisms where the functions of ncRNAs concentrated: oxidative phosphorylation, autophagy, apoptosis, drug target changes, and some signaling pathways. Also, these effects of ncRNAs in drug resistance were divided into two aspects. How ncRNAs regulate drug resistance in GIST was further summarized according to ncRNA types, different drugs and categories of resistance. Moreover, clinical applications of these ncRNAs in GIST chemotherapies concentrated on the prognostic biomarkers and novel therapeutic targets.
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Affiliation(s)
- Jiehan Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuning Guo
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Yang Fu, ; Zhenqiang Sun,
| | - Yang Fu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China
- *Correspondence: Yang Fu, ; Zhenqiang Sun,
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Zhang H, Liu Q. Prognostic Indicators for Gastrointestinal Stromal Tumors: A Review. Transl Oncol 2020; 13:100812. [PMID: 32619820 PMCID: PMC7327422 DOI: 10.1016/j.tranon.2020.100812] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/25/2020] [Accepted: 05/27/2020] [Indexed: 02/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are potentially malignancies that can occur anywhere in the digestive tract. Tyrosine kinase inhibitors (TKIs) such as imatinib have proven effective since the discovery of KIT and PDGFRA. The current version of NCNN, ESMO and EURACAN guidelines recognized that the three main prognostic factors are the mitotic rate, tumor size and tumor site. In addition, tumor rupture is also recognized as an independent risk factor. However, recent evidence shows that various types of gene mutations are associated with prognosis, and influencing factors such as gastrointestinal bleeding and high Ki67 index have been associated with poor prognosis. It shows that the current risk classification is still insufficient and controversial. With the emergence of more and more lack mutation in KIT/PDGFRA GISTs (KIT/PDGFRA wild-type GISTs) or drug resistance genes, primary and secondary drug resistance problems are caused, which makes the treatment of late or metastatic GIST face challenges. Therefore, this article will review the clinicopathological characteristics of GIST, the special molecular subtypes and other factors that may affect prognosis. We will also explore reliable prognostic markers for better postoperative management and improve the prognosis of patients with GIST.
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Affiliation(s)
- Haixin Zhang
- Department of Trauma center, The First Hospital of China Medical University, Shenyang, China
| | - Qi Liu
- Department of Trauma center, The First Hospital of China Medical University, Shenyang, China.
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Arshad J, Ahmed J, Subhawong T, Trent JC. Progress in determining response to treatment in gastrointestinal stromal tumor. Expert Rev Anticancer Ther 2020; 20:279-288. [PMID: 32191549 DOI: 10.1080/14737140.2020.1745068] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Gastrointestinal stromal tumor (GIST) is the most common malignant mesenchymal tumor of the gastrointestinal system. Multiple advances in the management of GIST from the discovery of KIT/PDGRA and other genetic alterations have led to the development of multiple tyrosine kinase inhibitors. Response assessment in GIST is determined with iRECIST (Response Evaluation Criteria in Solid Tumors), PERCIST (PET response criteria in solid tumors), or Choi criteria. Molecular genotyping of the tissue samples is the recent standard for diagnosis, treatment, and response to treatment.Areas covered: In this study, we provide a brief overview of the history of the GIST, molecular sequencing, available treatment options and clinical trials, radiologic response assessment, and the role of ctDNA in response evaluation.Expert opinion: Future GIST management is related to the development of sensitive assays to detect genetic alterations for initial diagnosis, treatment selection, monitoring the response to treatment, resistant mutations, and predicting survival.
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Affiliation(s)
- Junaid Arshad
- Miller School of Medicine/Sylvester Comprehensive Cancer Centre, University of Miami, Miami, FL, USA
| | - Jibran Ahmed
- Department of Hematology and Medical Oncology, Westchester Medical Center, Valhalla, NY, USA
| | - Ty Subhawong
- Miller School of Medicine/Sylvester Comprehensive Cancer Centre, University of Miami, Miami, FL, USA
| | - Jonathan C Trent
- Miller School of Medicine/Sylvester Comprehensive Cancer Centre, University of Miami, Miami, FL, USA
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Liu P, Tan F, Liu H, Li B, Lei T, Zhao X. The Use of Molecular Subtypes for Precision Therapy of Recurrent and Metastatic Gastrointestinal Stromal Tumor. Onco Targets Ther 2020; 13:2433-2447. [PMID: 32273716 PMCID: PMC7102917 DOI: 10.2147/ott.s241331] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/10/2020] [Indexed: 12/19/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor in the digestive tract. Tyrosine kinase inhibitors (TKIs), represented by imatinib, sunitinib, and regorafenib, have become the main treatment for recurrent and metastatic GISTs. With the wide application of mutation analysis and the precision medicine, molecular characteristics have been determined that not only predict the prognosis of patients with recurrent and metastatic GISTs, but also are closely related to the efficacy of first-, second- and third-line TKIs for GISTs, as well as other TKIs. Despite the significant effects of TKIs, the emergence of primary and secondary resistance ultimately leads to treatment failure and tumor progression. Currently, due to the signal transmission of KIT/PDGFRA during onset and tumor progression, strategies to counteract drug resistance include the replacement of TKIs and the development of new drugs that are directed towards carcinogenic mutations. In addition, it is also the embodiment of precision medicine for GISTs to explore new carcinogenic mechanisms and develop new drugs relying on new biotechnology. Surgery can benefit specific patients but its major purpose is to diminish the resistant clones. However, the prognosis of recurrent and metastatic patients is still unsatisfactory. Therefore, it is worth paying attention to how to maximize the benefits for patients.
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Affiliation(s)
- Peng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Fengbo Tan
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Heli Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Bin Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha410008, Hunan, People’s Republic of China
| | - Tianxiang Lei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Xianhui Zhao
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
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Liu W, Zeng X, Yin Y, Li C, Yang W, Wan W, Shi L, Wang G, Tao K, Zhang P. Targeting the WEE1 kinase strengthens the antitumor activity of imatinib via promoting KIT autophagic degradation in gastrointestinal stromal tumors. Gastric Cancer 2020; 23:39-51. [PMID: 31197522 DOI: 10.1007/s10120-019-00977-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 06/04/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Activating mutation of KIT or PDGFRA is the primary molecular mechanism for gastrointestinal stromal tumors (GISTs). Although imatinib has a revolutionary effect on GIST therapeutics, the benefits are not durable. Increasing reports have demonstrated that cell cycle checkpoint plays critical roles in GIST. Here, we explore the role of WEE1 kinase in GIST progression. METHODS Oncomine public database, western blotting, and immunohistochemistry were used to analyze WEE1 expression in GISTs. Using MTT assays, colony formation analysis, and flow cytometry, we examined the role of WEE1 in GIST cells and the antitumor activity of the inhibitor MK1775 alone, or in combination with imatinib. Cycloheximide chase assay and pharmacological inhibition of autophagy and proteasome pathway were performed to analyze KIT expression. Additionally, autophagic markers Beclin1 and LC3B were detected by western blotting. RESULTS Upregulated WEE1 expression was observed in GIST tissues and correlated with tumor size, mitotic count, and risk grade. Inhibition of WEE1 significantly suppressed GIST cell proliferation, induced apoptosis and cell cycle arrest. Imatinib and MK1775 co-treatment markedly enhanced the antitumor activity. Targeting WEE1 decreased the expression of KIT expression. Moreover, WEE1 stabilized KIT protein and KIT reduction observed upon WEE1 inhibition could be reversed by pharmacological inhibition of autophagy, but not proteasome pathway. WEE1 inhibition also increased Beclin1 expression and LC3B II/I ratio in GIST cells. CONCLUSIONS Our data suggest that WEE1 plays a pivotal role in GIST proliferation. WEE1 inhibition could promote KIT autophagic degradation and, therefore, targeting WEE1 might represent a novel strategy for GIST therapies.
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Affiliation(s)
- Weizhen Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiangyu Zeng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yuping Yin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chengguo Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wenchang Yang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wenze Wan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Liang Shi
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Peng Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Kalfusova A, Linke Z, Kalinova M, Krskova L, Hilska I, Szabova J, Vicha A, Kodet R. Gastrointestinal stromal tumors – Summary of mutational status of the primary/secondary KIT/PDGFRA mutations, BRAF mutations and SDH defects. Pathol Res Pract 2019; 215:152708. [DOI: 10.1016/j.prp.2019.152708] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/18/2019] [Accepted: 10/19/2019] [Indexed: 02/08/2023]
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Kurita S, Miyamoto R, Tani H, Kobayashi M, Sasaki T, Tamura K, Bonkobara M. Genetic alterations of KIT during clonal expansion and subsequent acquisition of resistance to toceranib in a canine mast cell tumor cell line. J Vet Pharmacol Ther 2019; 42:673-681. [PMID: 31553064 DOI: 10.1111/jvp.12816] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 08/09/2019] [Accepted: 09/03/2019] [Indexed: 12/16/2022]
Abstract
One of the potential mechanisms underlying acquired resistance to toceranib in canine mast cell tumor (MCT) is the emergence of a secondary mutation in the KIT gene. Here, genetic alterations of KIT during clonal expansion and subsequent acquisition of resistance to toceranib were investigated in the toceranib-susceptible canine MCT cell line VI-MC, which carries a KIT-activating mutation resulting in a predicted p.(Asn508Ile) amino acid change in the receptor tyrosine kinase protein KIT. Two sublines were cloned from VI-MC and toceranib-resistant sublines then were established by continuous exposure to toceranib. The mutation status of KIT in parental VI-MC and its sublines was investigated using next-generation sequencing (NGS). Additionally, effects of secondary mutations on toceranib sensitivity in p.(Asn508Ile)-mutant KIT were examined. KIT secondary mutations, including those encoding p.(Asn679Lys)-, p.(Asp819Val)-, and p.(Asp819Gly)-mutant KIT, that confer toceranib insensitivity to p.(Asn508Ile)-mutant KIT emerged only in toceranib-resistant VI-MCs. These mutations were not detected by NGS in the parental VI-MC line or in the toceranib-naive cloned VI-MCs, although the parental line and sublines exhibited genetic heterogeneity in KIT that may have been caused by genetic evolution during clonal expansion. VI-MC clones with these secondary mutations in KIT appear to have arisen from subclones during treatment with toceranib rather than being pre-existing. However, further study using a higher resolution technique will be needed to confirm the developmental mechanism of KIT secondary mutation in canine MCT cells with acquired resistance to toceranib.
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Affiliation(s)
- Sena Kurita
- Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Ryo Miyamoto
- Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Hiroyuki Tani
- Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Masato Kobayashi
- Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Takashi Sasaki
- Animal Research Center, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kyoichi Tamura
- Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Makoto Bonkobara
- Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan
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16
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Prognostication in Mesenchymal Tumors: Can We Improve? Surg Pathol Clin 2019; 12:217-225. [PMID: 30709445 DOI: 10.1016/j.path.2018.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Prognostication in mesenchymal tumors can be challenging. They exhibit diverse, and sometimes overlapping, histologic features that are not always predictive of their true behavior. This article highlights examples of both traditional and emerging sarcoma biomarkers.
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17
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Vincenzi B, Nannini M, Fumagalli E, Bronte G, Frezza AM, De Lisi D, Spalato Ceruso M, Santini D, Badalamenti G, Pantaleo MA, Russo A, Dei Tos AP, Casali P, Tonini G. Imatinib dose escalation versus sunitinib as a second line treatment in KIT exon 11 mutated GIST: a retrospective analysis. Oncotarget 2018; 7:69412-69419. [PMID: 26416414 PMCID: PMC5342487 DOI: 10.18632/oncotarget.5136] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
We retrospectively reviewed data from 123 patients (KIT exon 11 mutated) who received sunitinib or dose-escalated imatinib as second line. All patients progressed on imatinib (400 mg/die) and received a second line treatment with imatinib (800 mg/die) or sunitinib (50 mg/die 4 weeks on/2 off or 37.5 mg/day). Deletion versus other KIT 11 mutation was recorded, correlated with clinical benefits. 64% received imatinib, 36% sunitinib. KIT exon 11 mutation was available in 94 patients. With a median follow-up of 61 months, median time to progression (TTP) in patients receiving sunitinib and imatinib was 10 (95% CI 9.7–10.9) and 5 months (95% CI 3.6–6.7) respectively (P = 0.012). No difference was found in overall survival (OS) (P = 0.883). In imatinib arm, KIT exon 11 deletions was associated with a shorter TTP (7 vs 17 months; P = 0.02), with a trend in OS (54 vs 71 months P = 0.063). No difference was found in patients treated with sunitinib (P = 0.370). A second line with sunitinib was associated with an improved TTP in KIT exon 11 mutated patients progressing on imatinib 400 mg/die. Deletions in exon 11 seemed to be correlated with worse outcome in patients receiving imatinib-based second line.
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Affiliation(s)
- Bruno Vincenzi
- Department of Oncology, University Campus Bio-Medico, Rome, Italy
| | - Margherita Nannini
- Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Elena Fumagalli
- Adult Mesenchymal Tumor Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Giuseppe Bronte
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | | | - Delia De Lisi
- Department of Oncology, University Campus Bio-Medico, Rome, Italy
| | | | - Daniele Santini
- Department of Oncology, University Campus Bio-Medico, Rome, Italy
| | - Giuseppe Badalamenti
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Maria Abbondanza Pantaleo
- Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Antonio Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Angelo Paolo Dei Tos
- Department of Oncology and Pathology, General Hospital of Treviso, Treviso, Italy
| | - Paolo Casali
- Adult Mesenchymal Tumor Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Giuseppe Tonini
- Department of Oncology, University Campus Bio-Medico, Rome, Italy
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18
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Zhang Z, Jiang T, Wang W, Piao D. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumor after failure with imatinib and sunitinib treatment: A meta-analysis. Medicine (Baltimore) 2017; 96:e8698. [PMID: 29310342 PMCID: PMC5728743 DOI: 10.1097/md.0000000000008698] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
AIMS This meta-analysis aimed to evaluate the safety and efficacy of regorafenib as a treatment for patients with advanced (metastatic and/or unresectable) gastrointestinal stromal tumor (AGIST) after developing resistance to imatinib and sunitinib. METHODS A literature search of databases such as PubMed, Embase, and Cochrane library was conducted up to February 2017. The pooled percentages and the corresponding 95% confidence intervals (CIs) were calculated using the Stata 11.0 software. RESULTS Four studies involving 243 patients with AGIST were included. Results revealed that approximately 49% (95% CI 30-67), 14% (95% CI 5-23), and 41% (95% CI 21-61) of patients with AGIST showed clinical benefit (including complete response), partial response, and stable disease, respectively, after regorafenib treatment, which was given after failure with imatinib and sunitinib treatments. No complete response was found in the included studies. Pooled progression-free survival was 6.58 months (95% CI 4.62-8.54). Hypertension (20%; 95% CI 7-33), hand-foot skin reaction (22%; 95% CI 17-27), and hypophosphatemia (18%; 95% CI 5-41) were common grade ≥3 regorafenib-related adverse events in patients treated with regorafenib after failure with imatinib and sunitinib treatments. CONCLUSIONS Forty-nine per cent of patients with AGIST benefited after regorafenib treatment after the development of resistance to imatinib and sunitinib. More studies should be performed to improve the clinical survival of patients with AGIST. Close monitoring and appropriate management of grade ≥3 regorafenib-related adverse events should be considered during treatment.
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Affiliation(s)
- Zhenan Zhang
- Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University
| | - Tao Jiang
- Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University
| | - Wensheng Wang
- Thoracic Surgery, Harbin Children's Hospital, Harbin, Heilongjiang Province, China
| | - Daxun Piao
- Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University
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Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors. Oncotarget 2017; 8:76712-76721. [PMID: 29100343 PMCID: PMC5652737 DOI: 10.18632/oncotarget.20816] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 08/23/2017] [Indexed: 12/30/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) with KIT or platelet-derived growth factor receptor alpha (PDGFRa) oncogenic driver gene mutations, respond to tyrosine kinase inhibitors (TKIs) including imatinib, sunitinib, and regorafenib. However, most patients develop TKI resistance; therefore, novel agents are required. We established three TKI-resistant GIST patient-derived xenograft (PDX) models for effective drug development. These were PDX models harboring primary and secondary KIT and additional mutations; KIT exon 11 (p.Y570_L576del), KIT exon 17 (p.D816E), and PTEN (p.T321fs) mutations in GIST-RX1 from a patient who was unresponsive to imatinib, sunitinib, and sorafenib, and KIT exon 11 (p.K550_splice) and KIT exon 14 (p.T670I) mutations in GIST-RX2 and KIT exon 9 (p.502_503insYA) and KIT exon 17 (p.D820E) mutations in GIST-RX4 from patients with imatinib and imatinib/sunitinib resistance, respectively. The histological features and mutation statuses of GIST PDXs were consistent with those of the original patient tumors, and the models showed TKI sensitivity comparable to clinical responses. Imatinib inhibited the KIT pathway in imatinib-sensitive GIST-T1 but not GIST-RX1, RX2, and RX4. These GIST PDX models will be useful for studying TKI resistance mechanisms and evaluating novel targeted agents in GIST.
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20
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Joglekar-Javadekar M, Van Laere S, Bourne M, Moalwi M, Finetti P, Vermeulen PB, Birnbaum D, Dirix LY, Ueno N, Carter M, Rains J, Ramachandran A, Bertucci F, van Golen KL. Characterization and Targeting of Platelet-Derived Growth Factor Receptor alpha (PDGFRA) in Inflammatory Breast Cancer (IBC). Neoplasia 2017; 19:564-573. [PMID: 28609680 PMCID: PMC5470553 DOI: 10.1016/j.neo.2017.03.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 03/09/2017] [Accepted: 03/13/2017] [Indexed: 01/05/2023] Open
Abstract
PURPOSE: Inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer due to its rapid onset and highly invasive nature. IBC carries 5- and 10-year disease-free survival rates of ~45% and <20%, respectively. Multiple studies demonstrate that in comparison with conventional breast cancer, IBC has a unique molecular identity. Here, we have identified platelet-derived growth factor receptor alpha (PDGFRA) as being uniquely expressed and active in IBC patient tumor cells. EXPERIMENTAL DESIGN: Here we focus on characterizing and targeting PDGFRA in IBC. Using gene expression, we analyzed IBC patient samples and compared them with non-IBC patient samples. Further, using IBC cells in culture, we determined the effect of small molecules inhibitors in both in vitro and in vivo assays. RESULTS: In IBC patients, we show more frequent PDGFRA activation signature than non-IBC samples. In addition, the PDGFRA activation signature is associated with shorter metastasis-free survival in both uni- and multivariate analyses. We also demonstrate that IBC cells express active PDGFRA. Finally, we show that PDGFRA targeting by crenolanib (CP-868-596), but not imatinib (STI571), two small molecule inhibitors, interferes with IBC cell growth and emboli formation in vitro and tumor growth in vivo. CONCLUSIONS: Our data suggest that PDGFRA may be a promising target for therapy in IBC.
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Affiliation(s)
- Madhura Joglekar-Javadekar
- The Laboratory for Cytoskeletal Physiology, Department of Biological Sciences, The University of Delaware, Newark, DE; The Center for Translational Cancer Research, The University of Delaware, Newark, DE
| | - Steven Van Laere
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Michael Bourne
- The Laboratory for Cytoskeletal Physiology, Department of Biological Sciences, The University of Delaware, Newark, DE; The Center for Translational Cancer Research, The University of Delaware, Newark, DE
| | - Manal Moalwi
- The Laboratory for Cytoskeletal Physiology, Department of Biological Sciences, The University of Delaware, Newark, DE; The Center for Translational Cancer Research, The University of Delaware, Newark, DE
| | - Pascal Finetti
- Department of Molecular Oncology, Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Institut Paoli-Calmettes (IPC), Marseille, France
| | - Peter B Vermeulen
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Daniel Birnbaum
- Department of Molecular Oncology, Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Institut Paoli-Calmettes (IPC), Marseille, France
| | - Luc Y Dirix
- Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Naoto Ueno
- Breast Cancer Translational Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | | | - Francois Bertucci
- Department of Molecular Oncology, Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, CNRS UMR725, Institut Paoli-Calmettes (IPC), Marseille, France
| | - Kenneth L van Golen
- The Laboratory for Cytoskeletal Physiology, Department of Biological Sciences, The University of Delaware, Newark, DE; The Center for Translational Cancer Research, The University of Delaware, Newark, DE; The Helen F. Graham Cancer Center, Newark, DE.
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21
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Farag S, Somaiah N, Choi H, Heeres B, Wang WL, van Boven H, Nederlof P, Benjamin R, van der Graaf W, Grunhagen D, Boonstra PA, Reyners AK, Gelderblom H, Steeghs N. Clinical characteristics and treatment outcome in a large multicentre observational cohort of PDGFRA exon 18 mutated gastrointestinal stromal tumour patients. Eur J Cancer 2017; 76:76-83. [DOI: 10.1016/j.ejca.2017.02.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 02/05/2017] [Accepted: 02/05/2017] [Indexed: 12/11/2022]
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Hwang SJ, Park HG, Park Y, Lee HJ. An α-quaternary chiral latam derivative, YH-304 as a novel broad-spectrum anticancer agent. Int J Oncol 2016; 49:2480-2486. [PMID: 27748805 DOI: 10.3892/ijo.2016.3726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/30/2016] [Indexed: 11/06/2022] Open
Abstract
Previously, we reported that α-quaternary chiral lactam derivatives have broad spectrum anticancer activity. However, the underlying molecular mechanisms and its relevance are largely unknown. In the present study, we report progress on α-quaternary chiral lactam analogues that address this, focusing on the novel analogue YH-304 as a candidate to broadly target human cancer cells. The effect of YH-304 on cell transformation was assessed by clonogenic assay in non-small cell lung cancer cells (NSCLCs) A549 and 226B. Proapoptotic activity of YH-304 was determined by TUNEL assay and cleaved PARP, cleaved caspase-9, and Bax as markers for apoptosis. The p53-dependency and therapeutic spectrum of YH-304 was assessed by western blot analysis, real-time PCR, and cell viability assays in cells expressing endogenous wild or mutant p53. The effect of YH-304 on angiogenesis in vivo was examined by bFGF-mediated angiogenesis assay in zebrafish. Finally, the effect of YH-304 on AKT and ERK activation (phosphorylation) as a putative mechanism underlying the effect of YH-304 on bFGF-mediated angiogenesis was assessed using western blotting. We found that YH-304 significantly decreases the colony-forming activities of both A549 and 226B cells, inducing cellular apoptosis. Unlike nutlin-3 (p53 pathway activator), YH-304 did not affect the expression levels of p53 and its target gene such as p21 and thus showed p53-independent anticancer activity with broad spectrum. In addition, YH-304 inhibited bFGF-induced angiogenesis in vivo through mediating AKT and ERK signaling pathway, which plays an important role in bFGF activation and angiogenesis. Taken together, our data indicate that YH-304 may represent a novel therapeutic option for the treatment of cancer in a p53-independent manner.
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Affiliation(s)
- Su Jung Hwang
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea
| | - Hyeung-Geun Park
- Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
| | - Yohan Park
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea
| | - Hyo-Jong Lee
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam 621-749, Republic of Korea
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The metal-organic framework MIL-101(Cr) as efficient adsorbent in a vortex-assisted dispersive solid-phase extraction of imatinib mesylate in rat plasma coupled with ultra-performance liquid chromatography/mass spectrometry: Application to a pharmacokinetic study. J Chromatogr A 2016; 1449:30-8. [DOI: 10.1016/j.chroma.2016.04.055] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Revised: 03/03/2016] [Accepted: 04/17/2016] [Indexed: 11/17/2022]
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24
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Gao NA, Guo NJ, Yu WZ, Wang XX, Sun JR, Yu N, Liu RT, Liu XD, Liu ZY, Feng R. Synchronous occurrence of gastrointestinal stromal tumor and acute myeloid leukemia: A case report and review of the literature. Oncol Lett 2016; 11:2977-2980. [PMID: 27123049 PMCID: PMC4840780 DOI: 10.3892/ol.2016.4353] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 12/04/2015] [Indexed: 01/11/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) originate from the mesenchymal tissue of the gastrointestinal tract. The pathogenesis of GIST is associated with the mutational activation of the receptor tyrosine kinase cluster of differentiation (CD)117 or platelet-derived growth factor receptor-α. Overall, ~60% of GISTs occur in the stomach. Clinically, GISTs may coexist with various types of cancer, including liver cancer, pancreatic tumors and lymphoma, either synchronously or metachronously. The present study reports the case of a patient with the synchronous occurrence of a CD117-positive GIST and acute myeloid leukemia. A 69-year-old man was hospitalized for heart palpitations and dizziness, and was diagnosed with acute myeloid leukemia (AML) by bone marrow aspiration and flow cytometry analysis. An abdominal computed tomograpy and gastroscopy revealed the presence of GIST. The patient received chemotherapy in combination with imatinib (400 mg/day), and the mass was removed 2 months later. To the best of our knowledge, the present study is the first reported case of the synchronous development of a CD117-positive GIST and AML. Additional studies are required in order to understand the association between GIST and hematological malignancies.
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Affiliation(s)
- N A Gao
- Department of Hematology, Central Hospital of Jinan, Shandong University School of Medicine, Jinan, Shandong 250013, P.R. China; Department of Hematology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Nong-Jian Guo
- Department of Hematology, Central Hospital of Jinan, Shandong University School of Medicine, Jinan, Shandong 250013, P.R. China
| | - Wen-Zheng Yu
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Xue-Xia Wang
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Jian-Rong Sun
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Ning Yu
- Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Ren-Tong Liu
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Xiao-Dan Liu
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Zeng-Yan Liu
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
| | - Rui Feng
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
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Balakrishnan A, Vyas A, Deshpande K, Vyas D. Pharmacological cyclin dependent kinase inhibitors: Implications for colorectal cancer. World J Gastroenterol 2016; 22:2159-2164. [PMID: 26900281 PMCID: PMC4734993 DOI: 10.3748/wjg.v22.i7.2159] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 12/04/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer accounts for a significant proportion of cancer deaths worldwide. The need to develop more chemotherapeutic agents to combat this disease is critical. Cyclin dependent kinases (CDKs), along with its binding partner cyclins, serve to control the growth of cells through the cell cycle. A new class of drugs, termed CDK inhibitors, has been studied in preclinical and now clinical trials. These inhibitors are believed to act as an anti-cancer drug by blocking CDKs to block the uncontrolled cellular proliferation that is hallmark of cancers like colorectal cancer. CDK article provides overview of the emerging drug class of CDK inhibitors and provides a list of ones that are currently in clinical trials.
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26
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Eide CA, O’Hare T. Chronic myeloid leukemia: advances in understanding disease biology and mechanisms of resistance to tyrosine kinase inhibitors. Curr Hematol Malig Rep 2015; 10:158-66. [PMID: 25700679 PMCID: PMC4447524 DOI: 10.1007/s11899-015-0248-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) remains a flagship for molecularly targeted therapy in cancer. This focused review highlights critical elements of the underlying biology of CML and provides a summary of the molecular mechanisms that lead to TKI resistance: BCR-ABL1 mutation-based resistance and therapy escape through alternative pathway activation despite inhibition of BCR-ABL1 tyrosine kinase activity. We direct attention to the most current manifestations of these issues, including emergence of pan-TKI-resistant BCR-ABL1 compound mutants, new strategies for identification and therapeutic targeting of alternative pathways, and the exciting, controversial topic of cessation of TKI therapy leading to durable treatment-free remissions for a subset of patients. Further gains in our understanding of the biology of Philadelphia chromosome-positive (Ph-positive) leukemia and mechanisms of resistance to BCR-ABL1 TKIs will benefit patients and also provide a blueprint for similar discovery in other cancers.
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MESH Headings
- Antineoplastic Agents/therapeutic use
- Drug Resistance, Neoplasm/drug effects
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/metabolism
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Molecular Targeted Therapy
- Mutation
- Protein Kinase Inhibitors/chemistry
- Protein Kinase Inhibitors/therapeutic use
- Protein-Tyrosine Kinases/antagonists & inhibitors
- Protein-Tyrosine Kinases/metabolism
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Affiliation(s)
- Christopher A. Eide
- Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA
- Howard Hughes Medical Institute, Portland, OR, USA
| | - Thomas O’Hare
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA
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Abou Al-Shaar H, Solimanie S, Azzam A, Amin T, Abu-Zaid A. Gastrointestinal stromal tumor of the adrenal gland:a case report and review of the literature. Endocr Pathol 2015; 26:27-32. [PMID: 25510634 DOI: 10.1007/s12022-014-9350-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastrointestinal stromal tumors (GISTs) are rare neoplasms of the gastrointestinal (GI) tract. The occurrence of these neoplasms ectopically outside the GI tract is extremely uncommon. Only one case of primary adrenal GIST has been reported in the literature. In this account, we report a second case of primary adrenal GIST in a 34-year-old male who presented with a 5-week history of gradually progressive left flank pain and early satiety. Whole-body positron emission tomography (PET)/computed tomography (CT) scan showed a 14 × 11 cm hypermetabolic (18)fluorodeoxyglucose (FDG)-avid mass lesion involving the left adrenal gland and dorsal part of the left hemi-diaphragm. Biopsy of the lesion revealed tumor cells that are immunoreactive to CD-117 and CD-34 and negative to CD-31, S-100, cytokeratin, desmin, and vimentin, features characteristic of GIST. The patient was given imatinib, which drastically decreased his complaints with almost complete resolution of the tumor on his last follow-up radiographic images. Primary left adrenal GIST is an extremely rare neoplasm and can be confused with GISTs arising from the greater curvature of the stomach. Imatinib therapy is optimal in the management of these tumors.
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Affiliation(s)
- Hussam Abou Al-Shaar
- College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh, 11533, Saudi Arabia
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Pagliarini R, Shao W, Sellers WR. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep 2015; 16:280-96. [PMID: 25680965 DOI: 10.15252/embr.201439949] [Citation(s) in RCA: 178] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
A key goal of cancer therapeutics is to selectively target the genetic lesions that initiate and maintain cancer cell proliferation and survival. While most cancers harbor multiple oncogenic mutations, a wealth of preclinical and clinical data supports that many cancers are sensitive to inhibition of single oncogenes, a concept referred to as 'oncogene addiction'. Herein, we describe the clinical evidence supporting oncogene addiction and discuss common mechanistic themes emerging from the response and acquired resistance to oncogene-targeted therapies. Finally, we suggest several opportunities toward exploiting oncogene addiction to achieve curative cancer therapies.
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Affiliation(s)
- Raymond Pagliarini
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Wenlin Shao
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - William R Sellers
- Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Huang L, Hu C, DI Benedetto M, Varin R, Liu J, Jin J, Wang L, Vannier JP, Janin A, Lu H, Li H. Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells. Oncol Lett 2014; 9:1287-1292. [PMID: 25663899 PMCID: PMC4315062 DOI: 10.3892/ol.2014.2819] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 10/15/2014] [Indexed: 01/08/2023] Open
Abstract
Multiple drug resistance remains an unsolved problem in cancer therapy. A previous study has demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of doxorubicin treatment in a mouse tumor model. In the present study, the cross-resistance and sensitivity of HMECd1 and HMECd2 established cell lines to anti-angiogenic drugs, particularly sunitinib, was explored. The results revealed that Dox treatment induced a significant increase in the breast cancer resistance protein (ABCG2) gene transcription and protein expression. This increase gave rise to a 4- to 5-fold increase in the half maximal inhibitory concentration of the HMECd1 and HMECd2 cells in response to sunitinib treatment in vitro. Functionally, the role of ABCG2 in the resistance to sunitinib was confirmed by the use of the ABCG2 inhibitors fumitremorgin C and diethylstilbestrol, which blocked cell resistance. The present study indicates that endothelial cells exhibit cross-resistance between cytotoxic drugs and anti-angiogenic drugs. This suggests that multiple drug resistance induced by chemotherapy in endothelial cells may affect the efficiency of anti-angiogenic drugs.
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Affiliation(s)
- Limin Huang
- Department of Oncology, People's Hospital of Guizhou Province, Guiyang, Guizhou 550000, P.R. China
| | - Chaoquan Hu
- Department of Surgery, Affiliated Hospital of Guiyang Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Mélanie DI Benedetto
- French Institute of Health and Medical Research, UMR-S 1165, University Institute of Hematology, Saint Louis Hospital, Paris 75010, France
| | - Rémi Varin
- Laboratory of MERCI (EA 3829), Faculty of Medicine and Pharmacy, University of Rouen, Rouen 76183, France
| | - Jielin Liu
- Department of Surgery, Affiliated Hospital of Guiyang Medical University, Guiyang, Guizhou 550004, P.R. China ; French Institute of Health and Medical Research, UMR-S 1165, University Institute of Hematology, Saint Louis Hospital, Paris 75010, France
| | - Jian Jin
- French Institute of Health and Medical Research, UMR-S 1165, University Institute of Hematology, Saint Louis Hospital, Paris 75010, France ; School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Li Wang
- French Institute of Health and Medical Research, UMR-S 1165, University Institute of Hematology, Saint Louis Hospital, Paris 75010, France
| | - Jean-Pierre Vannier
- Laboratory of MERCI (EA 3829), Faculty of Medicine and Pharmacy, University of Rouen, Rouen 76183, France
| | - Anne Janin
- French Institute of Health and Medical Research, UMR-S 1165, University Institute of Hematology, Saint Louis Hospital, Paris 75010, France ; Laboratory of Pathology, Paris Diderot University, Sorbonne Paris Cité, UMR-S 1165, France ; Saint-Louis Hospital, Laboratory of Pathology, Paris 75010, France
| | - He Lu
- French Institute of Health and Medical Research, UMR-S 1165, University Institute of Hematology, Saint Louis Hospital, Paris 75010, France ; Laboratory of Pathology, Paris Diderot University, Sorbonne Paris Cité, UMR-S 1165, France
| | - Hong Li
- Laboratory of MERCI (EA 3829), Faculty of Medicine and Pharmacy, University of Rouen, Rouen 76183, France
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Association of ABCG2 polymorphism with clinical efficacy of imatinib in patients with gastrointestinal stromal tumor. Cancer Chemother Pharmacol 2014; 75:173-82. [DOI: 10.1007/s00280-014-2630-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Accepted: 11/14/2014] [Indexed: 12/29/2022]
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Wu L, Zhang Z, Yao H, Liu K, Wen Y, Xiong L. Clinical efficacy of second-generation tyrosine kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors: a meta-analysis of recent clinical trials. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 8:2061-7. [PMID: 25378911 PMCID: PMC4219427 DOI: 10.2147/dddt.s63840] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Primary and secondary resistance to imatinib, a selective receptor tyrosine kinase inhibitor (TKI), is a serious clinical problem in the control of advanced gastrointestinal stromal tumors (GIST). Here we report on a meta-analysis we performed to evaluate the efficacy of second-generation TKIs in the treatment of patients with imatinib-resistant GIST. METHODS Randomized controlled trials evaluating the clinical efficacy of second-generation TKIs were identified by searching PubMed and EMBASE from 2000 to February 2014. Outcomes subjected to analysis were progression-free survival and overall survival. Statistical analyses were performed using Review Manager version 5.1.0 (Cochrane Collaboration, Oxford, UK). Weighted hazard ratios (HR) with 95% confidence intervals (CIs) were calculated for the outcomes. Fixed-effects or random-effects models were used, depending on the degree of heterogeneity across the selected studies. RESULTS Three randomized controlled trials were selected for meta-analysis. Among imatinib-resistant or imatinib-intolerant patients, 541 received second-generation TKIs (sunitinib, nilotinib, or regorafenib) and 267 controls received placebo or best supportive care. Progression-free survival was significantly improved in the TKI-treated group (HR 0.38; 95% CI 0.24-0.59; P<0.0001). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.85; 95% CI 0.71-1.03; P=0.09). In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, TKI therapy (nilotinib or regorafenib) improved progression-free survival (HR 0.40; 95% CI 0.19-0.84; P=0.02) but not overall survival (HR 0.83; 95% CI 0.63-1.08; P=0.17). Regorafenib was shown to be effective in terms of progression-free survival across different subpopulations of patients who were resistant to both imatinib and sunitinib. CONCLUSION Second-generation TKIs (sunitinib, nilotinib, and regorafenib) are effective in improving progression-free survival but not overall survival in patients with GIST who are resistant or intolerant to imatinib or to imatinib and sunitinib. Regorafenib is promising as a third-line treatment option for patients with advanced GIST.
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Affiliation(s)
- Lile Wu
- Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
| | - Zhongqiang Zhang
- Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
| | - Hongliang Yao
- Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
| | - Kuijie Liu
- Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
| | - Yu Wen
- Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
| | - Li Xiong
- Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China
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Judson I, Scurr M, Gardner K, Barquin E, Marotti M, Collins B, Young H, Jürgensmeier JM, Leahy M. Phase II study of cediranib in patients with advanced gastrointestinal stromal tumors or soft-tissue sarcoma. Clin Cancer Res 2014; 20:3603-12. [PMID: 24714778 DOI: 10.1158/1078-0432.ccr-13-1881] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Cediranib is a potent VEGF signaling inhibitor with activity against all three VEGF receptors and KIT. This phase II study evaluated the antitumor activity of cediranib in patients with metastatic gastrointestinal stromal tumor (GIST) resistant/intolerant to imatinib, or metastatic soft-tissue sarcomas (STS; ClinicalTrials.gov, NCT00385203). EXPERIMENTAL DESIGN Patients received cediranib 45 mg/day. Primary objective was to determine the antitumor activity of cediranib according to changes in 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)FDG-PET) tumor uptake in patients with GIST using maximum standardized uptake values (SUVmax). Secondary objectives included objective tumor response and tolerability in patients with GIST/STS. RESULTS Thirty-four of 36 enrolled patients were treated (GIST n = 24; STS n = 10). At day 29, five patients had confirmed decreases in SUVmax (≥10% from day 8) and two had confirmed partial metabolic responses (≥25% decrease), but arithmetic mean percentage changes in SUVmax, averaged across the cohort, were not significant at day 8 [6.8%; 95% confidence interval (CI), 19.95-33.54) or day 29 (4.6%; 95% CI, 8.05-17.34). Eleven patients with GIST achieved a best objective tumor response of stable disease; eight achieved stable disease ≥16 weeks. In patients with STS, four of six with alveolar soft-part sarcoma (ASPS) achieved confirmed and durable partial responses. The commonest adverse events were diarrhea (85%), fatigue (74%), and hypertension (68%). CONCLUSIONS In patients progressing on imatinib/sunitinib, cediranib 45 mg/day demonstrated evidence of activity by (18)FDG-PET, but did not reduce average SUVmax. Evidence of antitumor activity was seen in ASPS.
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Affiliation(s)
- Ian Judson
- Authors' Affiliations: Royal Marsden Hospital, London;
| | | | - Kate Gardner
- Authors' Affiliations: Royal Marsden Hospital, London
| | | | | | | | | | | | - Michael Leahy
- Christie Hospital NHS Foundation Trust, Manchester, United Kingdom
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Dobbelstein M, Moll U. Targeting tumour-supportive cellular machineries in anticancer drug development. Nat Rev Drug Discov 2014; 13:179-96. [DOI: 10.1038/nrd4201] [Citation(s) in RCA: 175] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Abstract
For a decade, the technologies behind DNA sequencing have improved rapidly in cost reduction and speed. Sequencing in large populations of cancer patients is leading to dramatic advances in our understanding of the cancer genome. The wide variety of cancer types sequenced and analyzed using these technologies has revealed many novel fundamental genetic mechanisms driving cancer initiation, progression, and maintenance. We have deepened our understanding of the signaling pathways, demonstrating disruption in epigenetic regulation and destabilization of the splicing machinery. The molecular mechanisms of resistance to targeted therapies are being elucidated for the first time. The translation of genome-scale variation into clinically actionable information is still in its infancy; nevertheless, insights from sequencing studies have led to the discovery of a variety of novel diagnostic biomarkers and therapeutic targets. Here, we review recent advances in cancer genomics and discuss what the new findings have taught us about cancer biology and, more importantly, how these new findings guide more effective diagnostic and treatment strategies.
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Affiliation(s)
- Linghua Wang
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030
| | - David A. Wheeler
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030
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Gao X, Shen K, Wang C, Ling J, Wang H, Fang Y, Shi Y, Hou Y, Qin J, Sun Y, Qin X. MiR-320a downregulation is associated with imatinib resistance in gastrointestinal stromal tumors. Acta Biochim Biophys Sin (Shanghai) 2014; 46:72-5. [PMID: 24217767 DOI: 10.1093/abbs/gmt118] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract. Though imatinib improves the outcome, drug resistance remains the major problem for extending patient survival. Genetic mutation of the drug targets is the known mechanism for imatinib resistance. However, it cannot explain all of the phenomena of imatinib resistance, and numerous additional mechanisms have been proposed to account for imatinib resistance in various model systems. In this study, we applied the SYBR-green quantitative polymerase chain reaction-based array approach to screen the differentially expressed miRNAs between primary GIST patients and imatinib-resistant patients. The selected candidate miRNAs were validated in a cohort of 12 GIST patients. We found that low expression of miR-320a was correlated with short time to imatinib resistance, and proposed the potential mechanism of miR-320a for imatinib resistance.
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Affiliation(s)
- Xiaodong Gao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Yang H, Shen C, Zhang B, Chen H, Chen Z, Chen J. Expression and clinicopathological significance of CD9 in gastrointestinal stromal tumor. J Korean Med Sci 2013; 28:1443-8. [PMID: 24133347 PMCID: PMC3792597 DOI: 10.3346/jkms.2013.28.10.1443] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Accepted: 08/12/2013] [Indexed: 02/06/2023] Open
Abstract
This study investigated the expression and clinicopathological significance of CD9 in gastrointestinal stromal tumor (GIST). Immunohistochemistry staining for CD9 was performed on tumor tissues from 74 GIST patients. The correlation with clinicopathological features, risk classification and prognosis was analyzed. CD9-positive staining comprised 59.5% (44/74) of the GIST patients. The CD9-positive expression rate of the sample was significantly associated with diameter (P = 0.028), mitotic counts (P = 0.035), risk classification (P = 0.018) and three-year recurrence-free survival (RFS) (P < 0.001). Cox proportional hazards regression (HR = 0.352; P = 0.015) showed that CD9 is an independent factor for post-operative RFS. The subgroup analysis showed that CD9 expression in gastric stromal tumor (GST) is significantly associated with diameter (P = 0.031), risk classification (P = 0.023) and three-year RFS (P = 0.001). The Cox proportional hazards regression (HR = 0.104; P = 0.006) also showed that CD9 is an independent factor for RFS of GST. However, CD9 expression does not have a statistically significant correlation with clinicopathological features, risk classification, and prognosis in non-GST. In conclusion, CD9 expression in GIST appears to be associated with the recurrence and/or metastasis of GIST patients, especially in GST, which may indicate the important role of CD9 in the malignant biological behavior and prognosis of GST.
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Affiliation(s)
- Hongxin Yang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Department of Gastrointestinal Surgery of the Affiliated Hospital of Guiyang Medical University, Guiyang, Guizhou Province, China
| | - Chaoyong Shen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Haining Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhixin Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiaping Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Tomasetti C, Demetri GD, Parmigiani G. Why tyrosine kinase inhibitor resistance is common in advanced gastrointestinal stromal tumors. F1000Res 2013; 2:152. [PMID: 24555070 PMCID: PMC3892920 DOI: 10.12688/f1000research.2-152.v1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/01/2013] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Most patients with advanced gastrointestinal stromal tumors (GIST) develop drug resistance to tyrosine kinase inhibitors (TKIs) within two years of starting therapy, whereas most chronic myeloid leukemia (CML) patients in chronic phase still exhibit disease control after a decade on therapy. This article aims to explain this divergence in long term outcomes. METHODS AND RESULTS By combining clinical and experimental observations with mathematical formulas we estimate that, in advanced GIST, the genetic changes responsible for resistance are generally already present at disease detection. CONCLUSION This result has relevant clinical implications by providing support for the exploration of combination therapies.
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Affiliation(s)
- Cristian Tomasetti
- Department of Biostatistics, Harvard School of Public Health, Boston MA, 02215, USA ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston MA, 02215, USA ; Current affiliation: Division of Biostatistics & Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD , 21205-2013 , USA ; Current affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205-2179 , USA
| | - George D Demetri
- Ludwig Center for Cancer Research at Dana-Farber Cancer Institute and Harvard Medical School, Boston MA, 02215, USA ; Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston MA, 02215, USA
| | - Giovanni Parmigiani
- Department of Biostatistics, Harvard School of Public Health, Boston MA, 02215, USA ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston MA, 02215, USA
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Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the digestive tract. In up to 90% of cases, they are characterized by activating mutations in the KIT or the PDGFRA gene. GIST represent a paradigm for successful targeted treatment with tyrosine kinase inhibitors (TKI). Since the approval of the TKI imatinib in 2002 the survival of patients with metastatic GIST has tripled. The next logical step was the concept of using imatinib in an adjuvant approach, which was recently shown to increase overall survival significantly. In both settings, the mutational status has high predictive implications. In detail, GIST with KIT exon 11 mutations show the best response rates with partial remission rates of up to 80%. In KIT exon 9 mutations, a doubled daily dose of 800 mg imatinib is now standard. The PDGFRA exon 18 mutation D842V has been shown to lead to primary resistance. The treatment strategy in GIST is driven by their molecular characterisation. Further research has increased our knowledge on resistance mechanisms in solid tumors against TKI. The number of patients with secondary resistance due to acquired KIT mutations is increasing with treatment duration. Strategies to address this situation are the introduction of novel pathway inhibitors targeting different levels of signal transduction pathways, such as the mTOR/Akt pathway, the RAS/RAF pathway, histone deacetylation, among others. Among the GIST without mutations in the common hot spot regions of KIT and PDGFRA, the so-called wildtype GIST, further genomic subgroups have been identified. One such subgroup carries inactivating germline mutations in the genes encoding succinate dehydrogenase B, C, or D. They are associated with the occurrence of paragangliomas, so-called Carney-Stratakis syndrome. Most frequently, these GIST are located in the stomach, showing an epithelioid phenotype and a multinodular growth pattern. They preferentially occur in young females and often show lymph node metastases, the latter being very unusual in sporadic GIST. In sporadic Carney's triad additional pulmonary chondromas are observed and there are no SDH mutations. Another small subgroup of sporadic GIST present with BRAF mutations as an alternative genomic event. Finally, very rare kindreds with germline mutations in either KIT or PDGFRA have been described who develop multiple GIST and depending on the mutational subtype mastocytosis, hyperpigmentation and/or dysphagia. In summary, the molecular characterisation of GIST has revolutionized their treatment due to increasing knowledge about the high relevance of predictive molecular typing in solid tumors.
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Affiliation(s)
- E Wardelmann
- Institut für Pathologie, Universitätsklinikum Köln, Kerpener Str. 62, 50924 Köln.
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Angelini S, Ravegnini G, Fletcher JA, Maffei F, Hrelia P. Clinical relevance of pharmacogenetics in gastrointestinal stromal tumor treatment in the era of personalized therapy. Pharmacogenomics 2013; 14:941-56. [DOI: 10.2217/pgs.13.63] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Todd JR, Becker TM, Kefford RF, Rizos H. Secondary c-Kit mutations confer acquired resistance to RTK inhibitors in c-Kit mutant melanoma cells. Pigment Cell Melanoma Res 2013; 26:518-26. [DOI: 10.1111/pcmr.12107] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Accepted: 04/11/2013] [Indexed: 12/22/2022]
Affiliation(s)
- Jason R. Todd
- Westmead Institute for Cancer Research; University of Sydney at Westmead Millennium Institute, Westmead Hospital; Westmead; NSW; Australia
| | - Therese M. Becker
- Westmead Institute for Cancer Research; University of Sydney at Westmead Millennium Institute, Westmead Hospital; Westmead; NSW; Australia
| | | | - Helen Rizos
- Westmead Institute for Cancer Research; University of Sydney at Westmead Millennium Institute, Westmead Hospital; Westmead; NSW; Australia
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Liang J, Wu YL, Chen BJ, Zhang W, Tanaka Y, Sugiyama H. The C-kit receptor-mediated signal transduction and tumor-related diseases. Int J Biol Sci 2013; 9:435-43. [PMID: 23678293 PMCID: PMC3654492 DOI: 10.7150/ijbs.6087] [Citation(s) in RCA: 167] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Accepted: 04/15/2013] [Indexed: 02/04/2023] Open
Abstract
As an important member of tyrosine kinase family, c-kit receptor causes specific expression of certain genes, regulates cell differentiation and proliferation, resists cell apoptosis, and plays a key role in tumor occurrence, development, migration and recurrence through activating the downstream signaling molecules following interaction with stem cell factor (SCF). The abnormality of SCF/c-kit signaling pathway is closely related to some certain tumors. The discovery of c-kit receptor-targeted drugs has promoted clinical-related cancer's diagnosis and treatment. In this paper, we review recent research progress on c-kit receptor-mediated signal transduction and its potential therapeutic application as a target in tumor-related diseases.
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Affiliation(s)
- Jing Liang
- Department of Biopharmaceutical Science, College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China
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Arne G, Nilsson B, Dalmo J, Kristiansson E, Arvidsson Y, Forssell-Aronsson E, Nilsson O, Ahlman H. Gastrointestinal stromal tumors (GISTs) express somatostatin receptors and bind radiolabeled somatostatin analogs. Acta Oncol 2013; 52:783-92. [PMID: 23116418 DOI: 10.3109/0284186x.2012.733075] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) can be effectively treated with tyrosine kinase inhibitors (TKIs). However, some patients with GIST develop drug resistance, and alternative treatment strategies are therefore needed. The aim of this study was to analyze the expression of somatostatin receptors (SSTR) in GIST as a target for peptide receptor-mediated radiotherapy (PRRT). MATERIAL AND METHODS Expression profiling of SSTR1-5 was performed on biopsies from 34 GISTs (16 gastric tumors, 15 small intestinal tumors, and three rectal tumors). SSTR scintigraphy ((111)In-octreotide) and measurement of (111)In activity in tumor specimens was performed in seven patients. Uptake and internalization of (177)Lu- octreotate was studied in primary cell cultures from two patients. RESULTS Quantitative PCR analysis showed expression of SSTR1 and SSTR2 in the majority of tumors, while SSTR3-5 were expressed at low levels. Immunohistochemical analysis confirmed the presence of SSTR1 and SSTR2 proteins in all GISTs, and SSTR3-5 in a subset of tumors. Diagnostic imaging by SSTR scintigraphy, using (111)In-octreotide, demonstrated tumor uptake of (111)In in three of six GIST patients. Measurement of (111)In activity in excised tumor specimens from five patients gave tumor-to-blood (T/B) activity ratios of between eight and 96. Tumor cells in primary culture (gastric and small intestinal GIST) specifically bound and internalized (177)Lu when incubated with the therapeutic compound (177)Lu-octreotate for 4-48 hours (p < 0.05). CONCLUSION Peptide receptor-mediated radiotherapy via SSTR may provide a novel treatment strategy in carefully selected GIST patients with TKI-resistant tumors.
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Affiliation(s)
- Gabriella Arne
- Department of Pathology, Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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Hsueh YS, Yen CC, Shih NY, Chiang NJ, Li CF, Chen LT. Autophagy is involved in endogenous and NVP-AUY922-induced KIT degradation in gastrointestinal stromal tumors. Autophagy 2012. [PMID: 23196876 PMCID: PMC3552885 DOI: 10.4161/auto.22802] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is a prototype of mutant KIT oncogene-driven tumor. Prolonged tyrosine kinase inhibitor (TKI) treatment may result in a resistant phenotype through acquired secondary KIT mutation. Heat shock protein 90 (HSP90AA1) is a chaperone protein responsible for protein maturation and stability, and KIT is a known client protein of HSP90AA1. Inhibition of HSP90AA1 has been shown to destabilize KIT protein by enhancing its degradation via the proteasome-dependent pathway. In this study, we demonstrated that NVP-AUY922 (AUY922), a new class of HSP90AA1 inhibitor, is effective in inhibiting the growth of GIST cells expressing mutant KIT protein, the imatinib-sensitive GIST882 and imatinib-resistant GIST48 cells. The growth inhibition was accompanied with a sustained reduction of both total and phosphorylated KIT proteins and the induction of apoptosis in both cell lines. Surprisingly, AUY922-induced KIT reduction could be partially reversed by pharmacological inhibition of either autophagy or proteasome degradation pathway. The blockade of autophagy alone led to the accumulation of the KIT protein, highlighting the role of autophagy in endogenous KIT turnover. The involvement of autophagy in endogenous and AUY922-induced KIT protein turnover was further confirmed by the colocalization of KIT with MAP1LC3B-, acridine orange- or SQSTM1-labeled autophagosome, and by the accumulation of KIT in GIST cells by silencing either BECN1 or ATG5 to disrupt autophagosome activity. Therefore, the results not only highlight the potential application of AUY922 for the treatment of KIT-expressing GISTs, but also provide the first evidence for the involvement of autophagy in endogenous and HSP90AA1 inhibitor-induced KIT degradation.
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Affiliation(s)
- Yuan-Shuo Hsueh
- Institute of Clinical Pharmacy and Pharmaceutical Science, National Cheng Kung University, Tainan, Taiwan
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Minárik G, Plank L, Lasabová Z, Szemes T, Burjanivová T, Szépe P, Buzalková V, Porubský D, Sufliarsky J. Spectrum of mutations in gastrointestinal stromal tumor patients - a population-based study from Slovakia. APMIS 2012; 121:539-48. [PMID: 23106360 DOI: 10.1111/apm.12019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Accepted: 09/25/2012] [Indexed: 01/23/2023]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract and are characterized by presence of mutations in tyrosine kinases cKIT (KIT) and PDGFRα (PDGFRA). Mutations identified are highly heterogeneous, but some mutations are associated with specific clinical features of the tumor. Samples from 278 GIST patients collected during the period 2004-2011 were screened for mutations in exons 9, 11, 13, and 17 of KIT and 12, 14 and 18 of PDGFRA. Results of mutation screening were summarized and tested for possible association with clinical parameters of tumors. Mutations were identified in 83.81% of patients. Most frequent mutations were found in KIT exon 11 reaching frequency of 62.95%. Other exons contributed to the mutation pool with frequencies 8.27%, 7.55%, 2.52%, 1.44%, 1.08%, and 0.00%, in decreasing order KIT exon 9, PDGRFA exons 18 and 12, KIT exon 13, PDGFRA exon 14, and KIT exon 17. General linear model analysis showed no effect of any individual analyzed mutation on the phenotypic variables, but we confirmed association between mutations KIT exon 9 p. 503-504_dup2, and PDGFRA exon 18 p. D842V and intestinal and gastric localization of tumors.
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Affiliation(s)
- Gabriel Minárik
- Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, Bratislava, Slovakia.
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Kim J, Hwang J, Jeong H, Song HJ, Shin J, Hur G, Park YW, Lee SH, Kim J. Promoter methylation status of VEGF receptor genes: a possible epigenetic biomarker to anticipate the efficacy of intracellular-acting VEGF-targeted drugs in cancer cells. Epigenetics 2012; 7:191-200. [PMID: 22395469 DOI: 10.4161/epi.7.2.18973] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
We evaluated whether the inhibitory effects of vascular endothelial growth factor (VEGF)-targeted drugs on the proliferation of cancer cells differed according to VEGF receptor (VEGFR) genes, Flt1 and KDR, promoter methylation status. Five hyper-VEGFR-methylation and six no-VEGFR-methylation cancer cells were used for the present study, together with human umbilical endothelial cells (HUVECs) as a control. No-VEGFR-methylation cancer cells showed higher expression of Flt1 and KDR than hyper-VEGFR-methylation cancer cells. Hyper-VEGFR-methylation cancer cells only showed increased expression and protein levels of Flt1 and KDR after treatment with the demethylase 5-aza-2'-deoxycytidine. Two drugs (a VEGF-specific-antibody, bevacizumab, and a KDR-specific-antibody) targeting extracellular VEGF-VEGFR signaling and two VEGF-specific-tyrosine kinase inhibitors (PTK/ZK and sunitinib) targeting intracellular VEGFR signaling were used in the cell proliferation assay. HUVECs showed dose- and time-dependent proliferation decrease with all tested drugs over a 72 h incubation period. No- or hyper-VEGFR-methylation cancer cells showed no significant proliferation differences after treatment with VEGF-specific-antibody or VEGFR2-specific-antibody. After PTK/ZK or sunitinib treatment, no-VEGFR-methylation cancer cells showed dose- or time-dependent decreases in proliferation. Hyper-VEGFR-methylation cancer cells also showed proliferation inhibition by VEGF-specific-tyrosine kinase inhibitors after demethylation of Flt1 and KDR. Proliferation inhibition synergistically increased after combination of demethylation with PTK/ZK in hyper-VEGF-methylation cancer cells. We observed that intracellular targeting of VEGF-VEGFR signaling could be more effective than extracellular targeting of the pathway in the suppression of proliferation of some cancer cells. In particular, the efficacy of intracellular targeting of VEGF-specific-tyrosine kinase inhibitors might be influenced by the epigenetic alteration of VEGFRs.
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Affiliation(s)
- Jeeyeon Kim
- Department of Neurology, Hospital and School of Medicine, Chungnam National University, Daejon, South Korea
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Laine E, Auclair C, Tchertanov L. Allosteric communication across the native and mutated KIT receptor tyrosine kinase. PLoS Comput Biol 2012; 8:e1002661. [PMID: 22927810 PMCID: PMC3426562 DOI: 10.1371/journal.pcbi.1002661] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Accepted: 07/12/2012] [Indexed: 11/18/2022] Open
Abstract
A fundamental goal in cellular signaling is to understand allosteric communication, the process by which signals originated at one site in a protein propagate dependably to affect remote functional sites. Here, we describe the allosteric regulation of the receptor tyrosine kinase KIT. Our analysis evidenced that communication routes established between the activation loop (A-loop) and the distant juxtamembrane region (JMR) in the native protein were disrupted by the oncogenic mutation D816V positioned in the A-loop. In silico mutagenesis provided a plausible way of restoring the protein communication detected in the native KIT by introducing a counter-balancing second mutation D792E. The communication patterns observed in the native and mutated KIT correlate perfectly with the structural and dynamical features of these proteins. Particularly, a long-distance effect of the D816V mutation manifested as an important structural re-organization of the JMR in the oncogenic mutant was completely vanished in the double mutant D816V/D792E. This detailed characterization of the allosteric communication in the different forms of KIT, native and mutants, was performed by using a modular network representation composed of communication pathways and independent dynamic segments. Such representation permits to enrich a purely mechanistic interaction-based model of protein communication by the introduction of concerted local atomic fluctuations. This method, validated on KIT receptor, may guide a rational modulation of the physiopathological activities of other receptor tyrosine kinases. The majority of functionally important biological processes are regulated by allosteric communication within individual proteins and across protein complexes. Receptor tyrosine kinases (RTKs) control signal transduction pathways and consequently represent a typical paradigm. The mutation-induced deregulation of RTK activity impairs crucial cellular physiological functions and causes serious human diseases. The present study focuses on the allosteric communication across the three-dimensional structure of the RTK KIT cytoplasmic region. Combining a mechanistic model of information transmission with the analysis of concerted local atomic fluctuations we examined and compared the communication profiles in the native and D816V-mutated proteins. This approach permitted to localize and visualize communication routes in the native KIT and revealed that these routes were disrupted in the mutant D816V. We proposed in silico mutagenesis as a mean to restore the communication detected in the native KIT. Our work sheds light on the allosteric communication in RTKs, a phenomenon playing an essential role in signaling pathways albeit experiments do not provide the atomic details of the path followed in going from one structural element to the other. A rational understanding of the molecular determinants underlying the effects of disease-related kinase mutations may contribute to the improvement of targeted therapies.
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Affiliation(s)
- Elodie Laine
- LBPA, CNRS - ENS de Cachan, LabEx LERMIT, Cachan, France
| | | | - Luba Tchertanov
- LBPA, CNRS - ENS de Cachan, LabEx LERMIT, Cachan, France
- * E-mail:
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Savonarola A, Palmirotta R, Guadagni F, Silvestris F. Pharmacogenetics and pharmacogenomics: role of mutational analysis in anti-cancer targeted therapy. THE PHARMACOGENOMICS JOURNAL 2012; 12:277-286. [PMID: 22760589 DOI: 10.1038/tpj.2012.28] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 05/10/2012] [Accepted: 05/23/2012] [Indexed: 12/18/2022]
Abstract
The goal of cancer pharmacogenomics is to obtain benefit from personalized approaches of cancer treatment and prevention. Recent advances in genomic research have shed light on the crucial role of genetic variants, mainly involving genes encoding drug-metabolizing enzymes, drug transporters and targets, in driving different treatment responses among individuals, in terms of therapeutic efficacy and safety. Although a considerable amount of new targeted agents have been designed based on a finely understanding of molecular alterations in cancer, a wide gap between pharmacogenomic knowledge and clinical application still persists. This review focuses on the relevance of mutational analyses in predicting individual response to antitumor therapy, in order to improve the translational impact of genetic information on clinical practice.
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Affiliation(s)
- A Savonarola
- Department of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro--Piazza Giulio Cesare 11, Bari, Italy.
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George S, Wang Q, Heinrich MC, Corless CL, Zhu M, Butrynski JE, Morgan JA, Wagner AJ, Choy E, Tap WD, Yap JT, Van den Abbeele AD, Manola JB, Solomon SM, Fletcher JA, von Mehren M, Demetri GD. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol 2012; 30:2401-7. [PMID: 22614970 PMCID: PMC3675695 DOI: 10.1200/jco.2011.39.9394] [Citation(s) in RCA: 199] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Accepted: 03/06/2012] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib. PATIENTS AND METHODS Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible. RESULTS From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction. CONCLUSION Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.
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Affiliation(s)
- Suzanne George
- Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute D1212, 450 Brookline Ave, Boston, MA, USA.
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Parkin B, Chugh R. Molecular pathology of gastrointestinal stromal tumors and implications for treatment and prognosis. Curr Probl Cancer 2012; 35:245-54. [PMID: 22118564 DOI: 10.1016/j.currproblcancer.2011.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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DiNitto JP, Wu JC. Molecular mechanisms of drug resistance in tyrosine kinases cAbl and cKit. Crit Rev Biochem Mol Biol 2011; 46:295-309. [PMID: 21539479 DOI: 10.3109/10409238.2011.578612] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The inhibition of protein kinases has gained general acceptance as an effective approach to treat a wide range of cancers. However, in many cases, prolonged administration of kinase inhibitors often leads to acquired resistance, and the therapeutic effect is subsequently diminished. The wealth of recent studies using biochemical, kinetic, and structural approaches have revealed the molecular basis for the clinically observed resistance. In this review, we highlight several of the most common molecular mechanisms that lead to acquired resistance to kinase inhibitors observed with the cAbl (cellular form of the Abelson leukemia virus tyrosine kinase) and the type III receptor tyrosine kinase cKit, including a newly identified mechanism resulting from accelerated kinase activation caused by mutations in the activation loop. Strategies to overcome the loss of drug sensitivity that represents a challenge currently facing the field and the emerging approaches to circumvent resistance are discussed.
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