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1
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Hwang YJ, Lee Y, Yu SJ, Hong SK, Yi NJ, Choi Y, Lee H, Chung W, Kim H. Correlation between CTNNB1 mutation status and tumour phenotype in hepatitis B virus-related hepatocellular carcinoma. Histopathology 2025; 86:547-558. [PMID: 39526926 DOI: 10.1111/his.15363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/26/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024]
Abstract
AIMS The frequency of CTNNB1 mutation, one of the most frequent genetic events in hepatocellular carcinoma (HCC), is lower in Asian countries and in hepatitis B virus (HBV)-related HCCs. In this study, we evaluated the prevalence and types of CTNNB1-mutation in HBV-related HCC and correlated the molecular status with the histomorphological and immunohistochemical features. METHODS AND RESULTS A total of 108 consecutive cases of treatment-naïve, surgically resected HBV-related HCCs were selected. Targeted sequencing for CTNNB1 exons 3, 7 and 8 was performed, and the results were correlated with the expression pattern of glutamine synthetase (GS), nuclear β-catenin expression status and the histomorphological characteristics of the tumour. CTNNB1 mutations were identified in 13% of HBV-related HCCs; of these cases, mutations were found in D32-S37 (7%), T41 (4%) and S45 (2%) of exon 3. None of the HCCs demonstrated alterations in exons 7 and 8. CTNNB1 mutation was strongly associated with diffuse strong GS expression (P < 0.001), nuclear β-catenin expression (P < 0.001) and the classic CTNNB1 morphology (P = 0.038). Diffuse strong GS expression was observed in 78.6% of the CTNNB1-mutated HCCs, and nuclear β-catenin expression was identified in 64.3% of these cases. The classic CTNNB1 morphology was observed in 57% of all CTNNB1-mutated HCCs. Furthermore, programmed death-ligand 1 (PD-L1) was less frequently expressed in HCCs with classic CTNNB1 morphology. CONCLUSIONS CTNNB1 mutation was observed in 13% of HBV-related HCCs in this Korean cohort, and was associated with diffuse strong GS expression, nuclear β-catenin expression and classic CTNNB1 morphology.
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Affiliation(s)
- Yoon Jung Hwang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yangkyu Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine; Biomedical Research Institute, Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyejung Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Wonju Chung
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
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2
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Guérin C, Tulasne D. Recording and classifying MET receptor mutations in cancers. eLife 2024; 13:e92762. [PMID: 38652103 PMCID: PMC11042802 DOI: 10.7554/elife.92762] [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: 09/14/2023] [Accepted: 04/04/2024] [Indexed: 04/25/2024] Open
Abstract
Tyrosine kinase inhibitors (TKI) directed against MET have been recently approved to treat advanced non-small cell lung cancer (NSCLC) harbouring activating MET mutations. This success is the consequence of a long characterization of MET mutations in cancers, which we propose to outline in this review. MET, a receptor tyrosine kinase (RTK), displays in a broad panel of cancers many deregulations liable to promote tumour progression. The first MET mutation was discovered in 1997, in hereditary papillary renal cancer (HPRC), providing the first direct link between MET mutations and cancer development. As in other RTKs, these mutations are located in the kinase domain, leading in most cases to ligand-independent MET activation. In 2014, novel MET mutations were identified in several advanced cancers, including lung cancers. These mutations alter splice sites of exon 14, causing in-frame exon 14 skipping and deletion of a regulatory domain. Because these mutations are not located in the kinase domain, they are original and their mode of action has yet to be fully elucidated. Less than five years after the discovery of such mutations, the efficacy of a MET TKI was evidenced in NSCLC patients displaying MET exon 14 skipping. Yet its use led to a resistance mechanism involving acquisition of novel and already characterized MET mutations. Furthermore, novel somatic MET mutations are constantly being discovered. The challenge is no longer to identify them but to characterize them in order to predict their transforming activity and their sensitivity or resistance to MET TKIs, in order to adapt treatment.
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Affiliation(s)
- Célia Guérin
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesLilleFrance
| | - David Tulasne
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesLilleFrance
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3
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Crepaldi T, Gallo S, Comoglio PM. The MET Oncogene: Thirty Years of Insights into Molecular Mechanisms Driving Malignancy. Pharmaceuticals (Basel) 2024; 17:448. [PMID: 38675409 PMCID: PMC11054789 DOI: 10.3390/ph17040448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 04/28/2024] Open
Abstract
The discovery and subsequent research on the MET oncogene's role in cancer onset and progression have illuminated crucial insights into the molecular mechanisms driving malignancy. The identification of MET as the hepatocyte growth factor (HGF) receptor has paved the path for characterizing the MET tyrosine kinase activation mechanism and its downstream signaling cascade. Over the past thirty years, research has established the importance of HGF/MET signaling in normal cellular processes, such as cell dissociation, migration, proliferation, and cell survival. Notably, genetic alterations that lead to the continuous activation of MET, known as constitutive activation, have been identified as oncogenic drivers in various cancers. The genetic lesions affecting MET, such as exon skipping, gene amplification, and gene rearrangements, provide valuable targets for therapeutic intervention. Moreover, the implications of MET as a resistance mechanism to targeted therapies emphasize the need for combination treatments that include MET inhibitors. The intriguing "flare effect" phenomenon, wherein MET inhibition can lead to post-treatment increases in cancer cell proliferation, underscores the dynamic nature of cancer therapeutics. In human tumors, increased protein expression often occurs without gene amplification. Various mechanisms may cause an overexpression: transcriptional upregulation induced by other oncogenes; environmental factors (such as hypoxia or radiation); or substances produced by the reactive stroma, such as inflammatory cytokines, pro-angiogenic factors, and even HGF itself. In conclusion, the journey to understanding MET's involvement in cancer onset and progression over the past three decades has not only deepened our knowledge, but has also paved the way for innovative therapeutic strategies. Selective pharmacological inactivation of MET stands as a promising avenue for achieving cancer remission, particularly in cases where MET alterations are the primary drivers of malignancy.
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Affiliation(s)
- Tiziana Crepaldi
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (T.C.); (S.G.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
| | - Simona Gallo
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (T.C.); (S.G.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
| | - Paolo Maria Comoglio
- IFOM ETS—The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milano, Italy
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4
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Zhang N, Li Y. Receptor tyrosine kinases: biological functions and anticancer targeted therapy. MedComm (Beijing) 2023; 4:e446. [PMID: 38077251 PMCID: PMC10701465 DOI: 10.1002/mco2.446] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 10/16/2024] Open
Abstract
Receptor tyrosine kinases (RTKs) are a class of protein kinases that play crucial roles in various cellular processes, including cell migration, morphological differentiation, cell growth, and angiogenesis. In humans, 58 RTKs have been identified and categorized into 20 distinct families based on the composition of their extracellular regions. RTKs are primarily activated by specific ligands that bind to their extracellular region. They not only regulate tumor transformation, proliferation, metastasis, drug resistance, and angiogenesis, but also initiate and maintain the self-renewal and cloning ability of cancer stem cells. Accurate diagnosis and grading of tumors with dysregulated RTKs are essential in clinical practice. There is a growing body of evidence supporting the benefits of RTKs-targeted therapies for cancer patients, and researchers are actively exploring new targets and developing targeted agents. However, further optimization of RTK inhibitors is necessary to effectively target the diverse RTK alterations observed in human cancers. This review provides insights into the classification, structure, activation mechanisms, and expression of RTKs in tumors. It also highlights the research advances in RTKs targeted anticancer therapy and emphasizes their significance in optimizing cancer diagnosis and treatment strategies.
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Affiliation(s)
- Nan Zhang
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
| | - Yongsheng Li
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
- Department of Medical OncologyChongqing University Cancer HospitalChongqingChina
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5
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Altintas DM, Comoglio PM. An Observatory for the MET Oncogene: A Guide for Targeted Therapies. Cancers (Basel) 2023; 15:4672. [PMID: 37760640 PMCID: PMC10526818 DOI: 10.3390/cancers15184672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
The MET proto-oncogene encodes a pivotal tyrosine kinase receptor, binding the hepatocyte growth factor (HGF, also known as scatter factor, SF) and governing essential biological processes such as organogenesis, tissue repair, and angiogenesis. The pleiotropic physiological functions of MET explain its diverse role in cancer progression in a broad range of tumors; genetic/epigenetic alterations of MET drive tumor cell dissemination, metastasis, and acquired resistance to conventional and targeted therapies. Therefore, targeting MET emerged as a promising strategy, and many efforts were devoted to identifying the optimal way of hampering MET signaling. Despite encouraging results, however, the complexity of MET's functions in oncogenesis yields intriguing observations, fostering a humbler stance on our comprehension. This review explores recent discoveries concerning MET alterations in cancer, elucidating their biological repercussions, discussing therapeutic avenues, and outlining future directions. By contextualizing the research question and articulating the study's purpose, this work navigates MET biology's intricacies in cancer, offering a comprehensive perspective.
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Affiliation(s)
| | - Paolo M. Comoglio
- IFOM ETS—The AIRC Institute of Molecular Oncology, 20139 Milano, Italy;
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6
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Tyler LC, Le AT, Chen N, Nijmeh H, Bao L, Wilson TR, Chen D, Simmons B, Turner KM, Perusse D, Kasibhatla S, Christiansen J, Dudek AZ, Doebele RC. MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC. Thorac Cancer 2022; 13:3032-3041. [PMID: 36101520 PMCID: PMC9626307 DOI: 10.1111/1759-7714.14656] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target ROS1 KD mutations, less is known about bypass signaling in TKI-resistant ROS1+ lung cancers. METHODS Utilizing a primary, patient-derived TPM3-ROS1 cell line (CUTO28), we derived an entrectinib-resistant line (CUTO28-ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a CD74-ROS1 NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK-2 entrectinib trial to determine the prevalence of MET amplification. RESULTS CUTO28-ER cells did not exhibit ROS1 KD mutations. MET TKIs inhibited proliferation and downstream signaling and MET transcription was elevated in CUTO28-ER cells. CUTO28-ER cells displayed extrachromosomal (ecDNA) MET amplification without MET activating mutations, exon 14 skipping, or fusions. The CD74-ROS1 patient samples illustrated MET amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib-resistant ROS1+ NSCLC STARTRK-2 patients with ctDNA analysis at enrollment and disease progression displayed MET amplification. CONCLUSIONS Treatment with ROS1-selective inhibitors may lead to MET-mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1-selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET-driven resistance.
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Affiliation(s)
- Logan C. Tyler
- Department of Medicine—Division of Medical OncologyUniversity of Colorado—Anschutz Medical CampusAuroraColoradoUSA
| | - Anh T. Le
- Department of Medicine—Division of Medical OncologyUniversity of Colorado—Anschutz Medical CampusAuroraColoradoUSA
| | - Nan Chen
- Department of Medicine—Division of Medical OncologyUniversity of Colorado—Anschutz Medical CampusAuroraColoradoUSA
| | - Hala Nijmeh
- Department of PathologyUniversity of Colorado—Anschutz Medical CampusAuroraColoradoUSA
| | - Liming Bao
- Department of PathologyUniversity of Colorado—Anschutz Medical CampusAuroraColoradoUSA
| | | | - David Chen
- Genentech, Inc.South San FranciscoCaliforniaUSA
| | | | | | | | | | | | - Arkadiusz Z. Dudek
- HealthPartners Cancer Center at Regions HospitalSt. PaulMinnesotaUSA,Department of Medicine—Division of Hematology, Oncologyand Transplantation University of MinnesotaMinneapolisMinnesotaUSA
| | - Robert C. Doebele
- Department of Medicine—Division of Medical OncologyUniversity of Colorado—Anschutz Medical CampusAuroraColoradoUSA
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7
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Giansanti P, Samaras P, Bian Y, Meng C, Coluccio A, Frejno M, Jakubowsky H, Dobiasch S, Hazarika RR, Rechenberger J, Calzada-Wack J, Krumm J, Mueller S, Lee CY, Wimberger N, Lautenbacher L, Hassan Z, Chang YC, Falcomatà C, Bayer FP, Bärthel S, Schmidt T, Rad R, Combs SE, The M, Johannes F, Saur D, de Angelis MH, Wilhelm M, Schneider G, Kuster B. Mass spectrometry-based draft of the mouse proteome. Nat Methods 2022; 19:803-811. [PMID: 35710609 PMCID: PMC7613032 DOI: 10.1038/s41592-022-01526-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/17/2022] [Indexed: 01/06/2023]
Abstract
The laboratory mouse ranks among the most important experimental systems for biomedical research and molecular reference maps of such models are essential informational tools. Here, we present a quantitative draft of the mouse proteome and phosphoproteome constructed from 41 healthy tissues and several lines of analyses exemplify which insights can be gleaned from the data. For instance, tissue- and cell-type resolved profiles provide protein evidence for the expression of 17,000 genes, thousands of isoforms and 50,000 phosphorylation sites in vivo. Proteogenomic comparison of mouse, human and Arabidopsis reveal common and distinct mechanisms of gene expression regulation and, despite many similarities, numerous differentially abundant orthologs that likely serve species-specific functions. We leverage the mouse proteome by integrating phenotypic drug (n > 400) and radiation response data with the proteomes of 66 pancreatic ductal adenocarcinoma (PDAC) cell lines to reveal molecular markers for sensitivity and resistance. This unique atlas complements other molecular resources for the mouse and can be explored online via ProteomicsDB and PACiFIC.
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Affiliation(s)
- Piero Giansanti
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Patroklos Samaras
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Yangyang Bian
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
- College of Life Science, Northwest University, Xi'an, China
| | - Chen Meng
- Bavarian Biomolecular Mass Spectrometry Center, Technical University of Munich, Freising, Germany
| | - Andrea Coluccio
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Martin Frejno
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Hannah Jakubowsky
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Sophie Dobiasch
- Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Institute of Radiation Medicine, Department of Radiation Sciences, Helmholtz Zentrum München, Neuherberg, Germany
- German Cancer Consortium (DKTK), Munich, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rashmi R Hazarika
- Population epigenetics and epigenomics, Technical University of Munich, Freising, Germany
- Institute of Advanced Study (IAS), Technical University of Munich, Freising, Germany
| | - Julia Rechenberger
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Julia Calzada-Wack
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Johannes Krumm
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Sebastian Mueller
- Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany
| | - Chien-Yun Lee
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Nicole Wimberger
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Ludwig Lautenbacher
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Zonera Hassan
- Medical Clinic and Policlinic II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Yun-Chien Chang
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Chiara Falcomatà
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Florian P Bayer
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Stefanie Bärthel
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Tobias Schmidt
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Roland Rad
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany
| | - Stephanie E Combs
- Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Institute of Radiation Medicine, Department of Radiation Sciences, Helmholtz Zentrum München, Neuherberg, Germany
- German Cancer Consortium (DKTK), Munich, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Matthew The
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
| | - Frank Johannes
- Population epigenetics and epigenomics, Technical University of Munich, Freising, Germany
- Institute of Advanced Study (IAS), Technical University of Munich, Freising, Germany
| | - Dieter Saur
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
- Chair of Translational Cancer Research and Institute for Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Martin Hrabe de Angelis
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Chair of Experimental Genetics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Mathias Wilhelm
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
- Computational Mass Spectrometry, Technical University of Munich, Freising, Germany
| | - Günter Schneider
- Medical Clinic and Policlinic II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- University Medical Center Göttingen, Department of General, Visceral and Pediatric Surgery, Göttingen, Germany
| | - Bernhard Kuster
- Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.
- Bavarian Biomolecular Mass Spectrometry Center, Technical University of Munich, Freising, Germany.
- German Cancer Consortium (DKTK), Munich, Germany.
- German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Institute of Advanced Study (IAS), Technical University of Munich, Freising, Germany.
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8
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Recondo G, Che J, Jänne PA, Awad MM. Targeting MET Dysregulation in Cancer. Cancer Discov 2020; 10:922-934. [PMID: 32532746 PMCID: PMC7781009 DOI: 10.1158/2159-8290.cd-19-1446] [Citation(s) in RCA: 136] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/31/2020] [Accepted: 04/16/2020] [Indexed: 11/16/2022]
Abstract
Aberrant MET signaling can drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET gene amplification, mutation, rearrangement, and overexpression. Improvements in biomarker discovery and testing have more recently enabled the selection of patients with MET-dependent cancers for treatment with potent, specific, and novel MET-targeting therapies. We review the known oncologic processes that activate MET, discuss therapeutic strategies for MET-dependent malignancies, and highlight emerging challenges in acquired drug resistance in these cancers. SIGNIFICANCE: Increasing evidence supports the use of MET-targeting therapies in biomarker-selected cancers that harbor molecular alterations in MET. Diverse mechanisms of resistance to MET inhibitors will require the development of novel strategies to delay and overcome drug resistance.
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Affiliation(s)
- Gonzalo Recondo
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Jianwei Che
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts
| | - Pasi A Jänne
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Mark M Awad
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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9
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Guo R, Luo J, Chang J, Rekhtman N, Arcila M, Drilon A. MET-dependent solid tumours - molecular diagnosis and targeted therapy. Nat Rev Clin Oncol 2020; 17:569-587. [PMID: 32514147 DOI: 10.1038/s41571-020-0377-z] [Citation(s) in RCA: 210] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2020] [Indexed: 12/14/2022]
Abstract
Attempts to develop MET-targeted therapies have historically focused on MET-expressing cancers, with limited success. Thus, MET expression in the absence of a genomic marker of MET dependence is a poor predictor of benefit from MET-targeted therapy. However, owing to the development of more sensitive methods of detecting genomic alterations, high-level MET amplification and activating MET mutations or fusions are all now known to be drivers of oncogenesis. MET mutations include those affecting the kinase or extracellular domains and those that result in exon 14 skipping. The activity of MET tyrosine kinase inhibitors varies by MET alteration category. The likelihood of benefit from MET-targeted therapies increases with increasing levels of MET amplification, although no consensus exists on the optimal diagnostic cut-off point for MET copy number gains identified using fluorescence in situ hybridization and, in particular, next-generation sequencing. Several agents targeting exon 14 skipping alterations are currently in clinical development, with promising data available from early-phase trials. By contrast, the therapeutic implications of MET fusions remain underexplored. Here we summarize and evaluate the utility of various diagnostic techniques and the roles of different classes of MET-targeted therapies in cancers with MET amplification, mutation and fusion, and MET overexpression.
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Affiliation(s)
- Robin Guo
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jia Luo
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jason Chang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Natasha Rekhtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria Arcila
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexander Drilon
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. .,Weill Cornell Medical College, New York, NY, USA.
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10
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Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? Br J Cancer 2020; 122:1124-1132. [PMID: 32042068 PMCID: PMC7156745 DOI: 10.1038/s41416-019-0723-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 12/18/2019] [Indexed: 01/07/2023] Open
Abstract
Cancer of unknown primary (CUP) affects a small percentage of the general population. Nonetheless, a substantial number of these patients have a poor prognosis and consequently succumb to their illness within a year of diagnosis. The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. This review will outline the biology of CUP by exploring the hallmarks of cancer in order to rationalise the complexities of this enigmatic syndrome. This approach will help the reader to understand where research efforts currently stand and the pitfalls of this quest.
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11
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Poliaková M, Felser A, Pierzchala K, Nuoffer JM, Aebersold DM, Zimmer Y, Zamboni N, Medová M. Metabolomics reveals tepotinib-related mitochondrial dysfunction in MET-activating mutations-driven models. FEBS J 2019; 286:2692-2710. [PMID: 30993872 DOI: 10.1111/febs.14852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 02/27/2019] [Accepted: 04/12/2019] [Indexed: 11/26/2022]
Abstract
Genetic aberrations in the hepatocyte growth factor receptor tyrosine kinase MET induce oncogenic addiction in various types of human cancers, advocating MET as a viable anticancer target. Here, we report that MET signaling plays an important role in conferring a unique metabolic phenotype to cellular models expressing MET-activating mutated variants that are either sensitive or resistant toward MET small molecule inhibitors. MET phosphorylation downregulated by the specific MET inhibitor tepotinib resulted in markedly decreased viability and increased apoptosis in tepotinib-sensitive cells. Moreover, prior to the induction of MET inhibition-dependent cell death, tepotinib also led to an altered metabolic signature, characterized by a prominent reduction of metabolite ions related to amino sugar metabolism, gluconeogenesis, glycine and serine metabolism, and of numerous TCA cycle-related metabolites such as succinate, malate, and citrate. Functionally, a decrease in oxygen consumption rate, a reduced citrate synthase activity, a drop in membrane potential, and an associated misbalanced mitochondrial function were observed exclusively in MET inhibitor-sensitive cells. These data imply that interference with metabolic state can be considered an early indicator of efficient MET inhibition and particular changes reported here could be explored in the future as markers of efficacy of anti-MET therapies.
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Affiliation(s)
- Michaela Poliaková
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Radiation Oncology, University of Bern, Switzerland
| | - Andrea Felser
- University Institute of Clinical Chemistry, Bern University Hospital, Switzerland
| | - Katarzyna Pierzchala
- Center for Biomedical Imaging (CIBM), EPFL SB CIBM - AIT/LIFMET, Lausanne, Switzerland
| | - Jean-Marc Nuoffer
- University Institute of Clinical Chemistry, Bern University Hospital, Switzerland
| | - Daniel Matthias Aebersold
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Radiation Oncology, University of Bern, Switzerland
| | - Yitzhak Zimmer
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Radiation Oncology, University of Bern, Switzerland
| | - Nicola Zamboni
- Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, Switzerland
| | - Michaela Medová
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Radiation Oncology, University of Bern, Switzerland
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12
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Zhu L, Xue F, Xu X, Xu J, Hu S, Liu S, Cui Y, Gao C. MicroRNA-198 inhibition of HGF/c-MET signaling pathway overcomes resistance to radiotherapy and induces apoptosis in human non-small-cell lung cancer. J Cell Biochem 2018; 119:7873-7886. [PMID: 29943841 DOI: 10.1002/jcb.27204] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/24/2018] [Indexed: 12/20/2022]
Abstract
Non-small-cell lung cancer (NSCLC) is the most common cause of death from cancer worldwide. MicroRNAs (miRNAs) are a group of important regulators in NSCLC, including miR-198. However, the underlying molecular mechanisms of miR-198 involvement in intrinsic resistance to radiotherapy in NSCLC remain to be elucidated. In this study, to investigate the clinical significance of miR-198 in NSCLC in relation to the response to radiotherapy, we determined the expression patterns of miR-198 between responders and nonresponders after 2 months of radiotherapy and found that decreased expressions of miR-198 were associated with radiotherapy resistance. In addition, we altered the endogenous miR-198 using mimics or inhibitors to examine the effects of miR-198 on 4-Gy-irradiated A549 and SPCA-1 cells in vitro. Upregulating miR-198 was shown to inhibit cell proliferation, migration, and invasion and induce apoptosis. MiR-198 inhibition produced a reciprocal result. PHA665752, a selective small-molecule c-Met inhibitor, potently inhibited hepatocyte growth factor (HGF)-stimulated and constitutive c-Met phosphorylation and rescued 4-Gy-irradiated A549 and SPCA-1 cells from miR-198 inhibition. Most importantly, we established tumor xenografts of 4-Gy-irradiated A549 and SPCA-1 cells in nude mice and found that miR-198 could suppress tumor formation. Hence, our data delineates the molecular pathway by which miR-198 inhibits NSCLC cellular proliferation and induces apoptosis following radiotherapy, providing a novel target aimed at improving the radiotherapeutic response in NSCLC.
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Affiliation(s)
- Lin Zhu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Feng Xue
- Department of Medical Oncology, Heilongjiang Provincial Hospital, Harbin, China
| | - Xiangying Xu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China.,The Third Affiliated Hospital of SUN YAT-SEN University, Guangzhou, China
| | - Jianyu Xu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Songliu Hu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shanshan Liu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ying Cui
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chunzi Gao
- The Second Ward of Oncology Department, The First Clinical Hospital affiliated to Harbin Medical University, Harbin, China
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13
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Anestis A, Zoi I, Karamouzis MV. Current advances of targeting HGF/c-Met pathway in gastric cancer. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:247. [PMID: 30069449 PMCID: PMC6046293 DOI: 10.21037/atm.2018.04.42] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/18/2018] [Indexed: 12/18/2022]
Abstract
Despite the advances in systemic chemotherapy, gastric adenocarcinoma (GC) remains the third most common cause of cancer-related deaths with poor prognosis. The heterogeneity of GC indicates that novel biomarkers should be established in order to further classify tumors and develop individual targeted therapies. High-quality preclinical and clinical research has demonstrated that growth factor (HGF)-hepatocyte growth factor receptor (c-Met) pathway plays a pivotal role on the growth, survival and invasiveness of GC. In particular, aberrant activation of HGF/c-Met signaling pathway has been associated with poor clinical outcomes, suggesting the therapeutic potential of c-Met. This has stimulated the development and evaluation of a number of c-Met targeted agents in an advance disease setting. In this review, we summarize the current state of the art in the advances on the inhibition of c-Met pathway, with particular emphasis on the clinical testing of c-Met targeted therapeutic agents. Furthermore, we discuss the challenges facing the incorporation of c-Met targeted agents in randomized trials, with the idea that the definition of the appropriate genetic and molecular context for the use of these agents remains the priority.
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Affiliation(s)
- Aristomenis Anestis
- Molecular Oncology Unit, Department of Biological Chemistry, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Ilianna Zoi
- Molecular Oncology Unit, Department of Biological Chemistry, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- First Department of Internal Medicine, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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14
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Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nat Genet 2018; 50:708-717. [PMID: 29686388 PMCID: PMC5934307 DOI: 10.1038/s41588-018-0105-0] [Citation(s) in RCA: 200] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 02/28/2018] [Indexed: 01/09/2023]
Abstract
To understand how genomic heterogeneity of glioblastoma contributes to the poor response to therapy characteristic of this disease, we performed DNA and RNA sequencing on GBM tumor samples and the neurospheres and orthotopic xenograft models derived from them. We used the resulting data set to show that somatic driver alterations including single nucleotide variants, focal DNA alterations, and oncogene amplification on extrachromosomal DNA (ecDNA) elements were in majority propagated from tumor to model systems. In several instances, ecDNAs and chromosomal alterations demonstrated divergent inheritance patterns and clonal selection dynamics during cell culture and xenografting. We infer that ecDNA inherited unevenly between offspring cells, a characteristic that affects the oncogenic potential of cells with more or fewer ecDNAs. Longitudinal patient tumor profiling found that oncogenic ecDNAs are frequently retained throughout the course of disease. Our analysis shows that extrachromosomal elements allow rapid increase of genomic heterogeneity during glioblastoma evolution, independent of chromosomal DNA alterations.
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15
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The multiple paths towards MET receptor addiction in cancer. Oncogene 2018; 37:3200-3215. [PMID: 29551767 DOI: 10.1038/s41388-018-0185-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 01/30/2018] [Accepted: 01/30/2018] [Indexed: 12/14/2022]
Abstract
Targeted therapies against receptor tyrosine kinases (RTKs) are currently used with success on a small proportion of patients displaying clear oncogene activation. Lung cancers with a mutated EGFR provide a good illustration. The efficacy of targeted treatments relies on oncogene addiction, a situation in which the growth or survival of the cancer cells depends on a single deregulated oncogene. MET, a member of the RTK family, is a promising target because it displays many deregulations in a broad panel of cancers. Although clinical trials having evaluated MET inhibitors in large populations have yielded disappointing results, many recent case reports suggest that MET inhibition may be effective in a subset of patients with unambiguous MET activation and thus, most probably, oncogene addiction. Interestingly, preclinical studies have revealed a particularity of MET addiction: it can arise through several mechanisms, and the mechanism involved can differ according to the cancer type. The present review describes the different mechanisms of MET addiction and their consequences for diagnosis and therapeutic strategies. Although in each cancer type MET addiction affects a restricted number of patients, pooling of these patients across all cancer types yields a targetable population liable to benefit from addiction-targeting therapies.
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16
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Stella GM, Benvenuti S, Gentile A, Comoglio PM. MET Activation and Physical Dynamics of the Metastatic Process: The Paradigm of Cancers of Unknown Primary Origin. EBioMedicine 2017; 24:34-42. [PMID: 29037604 PMCID: PMC5652293 DOI: 10.1016/j.ebiom.2017.09.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 09/05/2017] [Accepted: 09/18/2017] [Indexed: 12/14/2022] Open
Abstract
The molecular and cellular mechanisms which drive metastatic spread are the topic of constant debate and scientific research due to the potential implications for cancer patients' prognosis. In addition to genetics and environmental factors, mechanics of single cells and physical interaction with the surrounding environment play relevant role in defining invasive phenotype. Reconstructing the physical properties of metastatic clones may help to clarify still open issues in disease progression as well as to lead to new diagnostic and therapeutic approaches. In this perspective cancer of unknown primary origin (CUP) identify the ideal model to study physical interactions and forces involved in the metastatic process. We have previously demonstrated that MET oncogene is mutated with unexpected high frequency in CUPs. We here analyze and discuss how the MET activation by somatic mutation may affect physical properties in giving rise to such a highly malignant syndrome, as that defined by CUP.
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Affiliation(s)
- Giulia M Stella
- Cardiothoracic Dept., Section of Respiratory System Diseases, IRCCS Policlinico San Matteo, Pavia, Italy.
| | - Silvia Benvenuti
- Candiolo Cancer Institute, FPO-IRCCS, Str Prov 142, 10060 Candiolo, Italy
| | - Alessandra Gentile
- Candiolo Cancer Institute, FPO-IRCCS, Str Prov 142, 10060 Candiolo, Italy
| | - Paolo M Comoglio
- Candiolo Cancer Institute, FPO-IRCCS, Str Prov 142, 10060 Candiolo, Italy
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17
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Tovar EA, Graveel CR. MET in human cancer: germline and somatic mutations. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:205. [PMID: 28603720 DOI: 10.21037/atm.2017.03.64] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Since the initial discovery of missense MET mutations in hereditary papillary renal carcinoma (HPRC), activating MET mutations have been identified in a diverse range of human cancers. MET mutations have been identified in several functional domains including the kinase, juxtamembrane, and Sema domains. Studies of these mutations have been invaluable for our understanding of the tumor initiating activity of MET, receptor tyrosine kinase (RTK) recycling and regulation, and mechanisms of resistance to kinase inhibition. These studies also demonstrate that mutationally activated MET plays a significant role in a wide range of cancers and RTKs can promote tumor progression through diverse mechanisms. This review will cover the various MET mutations that have been identified, their mechanism of action, and the significant role that mutationally-activated MET plays in tumor initiation, progression, and therapeutic resistance.
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Affiliation(s)
- Elizabeth A Tovar
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Carrie R Graveel
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA
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18
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Cortot AB, Kherrouche Z, Descarpentries C, Wislez M, Baldacci S, Furlan A, Tulasne D. Exon 14 Deleted MET Receptor as a New Biomarker and Target in Cancers. J Natl Cancer Inst 2017; 109:2982828. [DOI: 10.1093/jnci/djw262] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 10/04/2016] [Indexed: 01/07/2023] Open
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19
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Huang F, Ma Z, Pollan S, Yuan X, Swartwood S, Gertych A, Rodriguez M, Mallick J, Bhele S, Guindi M, Dhall D, Walts AE, Bose S, de Peralta Venturina M, Marchevsky AM, Luthringer DJ, Feller SM, Berman B, Freeman MR, Alvord WG, Vande Woude G, Amin MB, Knudsen BS. Quantitative imaging for development of companion diagnostics to drugs targeting HGF/MET. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2016; 2:210-222. [PMID: 27785366 PMCID: PMC5068192 DOI: 10.1002/cjp2.49] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023]
Abstract
The limited clinical success of anti-HGF/MET drugs can be attributed to the lack of predictive biomarkers that adequately select patients for treatment. We demonstrate here that quantitative digital imaging of formalin fixed paraffin embedded tissues stained by immunohistochemistry can be used to measure signals from weakly staining antibodies and provides new opportunities to develop assays for detection of MET receptor activity. To establish a biomarker panel of MET activation, we employed seven antibodies measuring protein expression in the HGF/MET pathway in 20 cases and up to 80 cores from 18 human cancer types. The antibodies bind to epitopes in the extra (EC)- and intracellular (IC) domains of MET (MET4EC, SP44_METIC, D1C2_METIC), to MET-pY1234/pY1235, a marker of MET kinase activation, as well as to HGF, pSFK or pMAPK. Expression of HGF was determined in tumour cells (T_HGF) as well as in stroma surrounding cancer (St_HGF). Remarkably, MET4EC correlated more strongly with pMET (r = 0.47) than SP44_METIC (r = 0.21) or D1C2_METIC (r = 0.08) across 18 cancer types. In addition, correlation coefficients of pMET and T_HGF (r = 0.38) and pMET and pSFK (r = 0.56) were high. Prediction models of MET activation reveal cancer-type specific differences in performance of MET4EC, SP44_METIC and anti-HGF antibodies. Thus, we conclude that assays to predict the response to HGF/MET inhibitors require a cancer-type specific antibody selection and should be developed in those cancer types in which they are employed clinically.
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Affiliation(s)
- Fangjin Huang
- Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Zhaoxuan Ma
- Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Sara Pollan
- Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Xiaopu Yuan
- Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Steven Swartwood
- Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Arkadiusz Gertych
- Departments of Surgery Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Maria Rodriguez
- Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Jayati Mallick
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Sanica Bhele
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Maha Guindi
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Deepti Dhall
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Ann E Walts
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Shikha Bose
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Mariza de Peralta Venturina
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Alberto M Marchevsky
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Daniel J Luthringer
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Stephan M Feller
- Institute of Molecular Medicine, Martin-Luther-University 06120 Halle Germany
| | - Benjamin Berman
- Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Michael R Freeman
- Department of Biomedical SciencesCedars-Sinai Medical CenterLos AngelesCalifornia90048USA; Departments of SurgeryCedars-Sinai Medical CenterLos AngelesCalifornia90048USA; Cancer Biology Program, Departments of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterLos AngelesCalifornia90048USA
| | - W Gregory Alvord
- Data Management Services, Inc., National Cancer Institute at Frederick Frederick Maryland 21702 USA
| | - George Vande Woude
- Laboratory of Molecular Oncology Center for Cancer and Cell Biology, Van Andel Research Institute Grand Rapids Michigan 49503 USA
| | - Mahul B Amin
- Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles California 90048 USA
| | - Beatrice S Knudsen
- Department of Biomedical SciencesCedars-Sinai Medical CenterLos AngelesCalifornia90048USA; Department of Pathology and Laboratory MedicineCedars-Sinai Medical CenterLos AngelesCalifornia90048USA
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20
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Chen J, Huang D, Rubera I, Futami K, Wang P, Zickert P, Khoo SK, Dykema K, Zhao P, Petillo D, Cao B, Zhang Z, Si S, Schoen SR, Yang XJ, Zhou M, Xiao GQ, Wu G, Nordenskjöld M, Tauc M, Williams BO, Furge KA, Teh BT. Disruption of tubular Flcn expression as a mouse model for renal tumor induction. Kidney Int 2015; 88:1057-69. [PMID: 26083655 DOI: 10.1038/ki.2015.177] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 04/09/2015] [Accepted: 04/16/2015] [Indexed: 01/07/2023]
Abstract
The study of kidney cancer pathogenesis and its treatment has been limited by the scarcity of genetically defined animal models. The FLCN gene that codes for the protein folliculin, mutated in Birt-Hogg-Dubé syndrome, presents a new target for mouse modeling of kidney cancer. Here we developed a kidney-specific knockout model by disrupting the mouse Flcn in the proximal tubules, thus avoiding homozygous embryonic lethality or neonatal mortality, and eliminating the requirement of loss of heterozygosity for tumorigenesis. This knockout develops renal cysts and early onset (6 months) of multiple histological subtypes of renal neoplasms featuring high tumor penetrance. Although the majority of the tumors were chromophobe renal cell carcinomas in affected mice under 1 year of age, papillary renal cell carcinomas predominated in the kidneys of older knockout mice. This renal neoplasia from cystic hyperplasia at 4 months to high-grade renal tumors by 16 months represented the progression of tumorigenesis. The mTOR and TGF-β signalings were upregulated in Flcn-deficient tumors, and these two activated pathways may synergetically cause renal tumorigenesis. Treatment of knockout mice with the mTOR inhibitor rapamycin for 10 months led to the suppression of tumor growth. Thus, our model recapitulates human Birt-Hogg-Dubé kidney tumorigenesis, provides a valuable tool for further study of Flcn-deficient renal tumorigenesis, and tests new drugs/approaches to their treatment.
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Affiliation(s)
- Jindong Chen
- Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.,Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi, China
| | - Dachuan Huang
- NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore, Singapore
| | | | - Kunihiko Futami
- Course of Applied Marine Biosciences, Graduate School of Marine Science and Technology, Tokyo University of Marine Science and Technology, Tokyo, Japan
| | - Pengfei Wang
- Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA
| | - Peter Zickert
- Department of Pathology, Karolinska Institutet, Danderyds Hospital, Stockholm, Sweden
| | - Sok-Kean Khoo
- Department of Cell and Molecular Biology, Grand Valley State University, Cook-DeVos Center for Health Sciences, Grand Rapids, MI, USA
| | - Karl Dykema
- Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Ping Zhao
- Spectrum Health, Helen DeVos Children's Hospital, Grand Rapids, MI, USA
| | - David Petillo
- Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA.,Molecular Diagnostics Program, College of Health Professions, Ferris State University, Grand Rapids, MI, USA
| | - Brian Cao
- Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Zhongfa Zhang
- Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Shuhui Si
- Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA
| | - Susan R Schoen
- Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA
| | - Ximing J Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ming Zhou
- Department of Pathology, New York University Medical Center, New York, NY, USA
| | - Guang-Qian Xiao
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
| | - Guan Wu
- Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA
| | - Magnus Nordenskjöld
- Clinical Genetics, Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michel Tauc
- University of Nice-Sophia Antipolis, Nice, France
| | - Bart O Williams
- Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Kyle A Furge
- Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Bin Tean Teh
- NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore, Singapore.,Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA
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21
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Petrini I. Biology of MET: a double life between normal tissue repair and tumor progression. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:82. [PMID: 25992381 DOI: 10.3978/j.issn.2305-5839.2015.03.58] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 01/28/2015] [Indexed: 01/30/2023]
Abstract
MNNG HOS transforming gene (MET) is a class IV receptor tyrosine kinase, expressed on the surface of epithelial cells. The interaction with the hepatocyte grow factor (HGF) induces MET dimerization and the activation of multiple intracellular pathways leading to cell proliferation, anti-apoptosis, morphogenic differentiation, motility, invasion, and angiogenesis. Knock out mice have demonstrated that MET is necessary for normal embryogenesis including the formation of striate muscles, liver and trophoblastic structures. The overexpression of MET and HGF are common in solid tumors and contribute to determine their growth. Indeed, MET has been cloned as a transforming gene from a chemically induced human osteosarcoma cell line and therefore is considered a proto-oncogene. Germline MET mutations are characteristic of hereditary papillary kidney cancers and MET amplification is observed in tumors including lung and gastric adenocarcinomas. The inhibition of MET signaling is the target for specific drugs that are raising exciting expectation for medical treatment of cancer.
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22
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The MET gene is a common integration target in avian leukosis virus subgroup J-induced chicken hemangiomas. J Virol 2015; 89:4712-9. [PMID: 25673726 DOI: 10.1128/jvi.03225-14] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 02/09/2015] [Indexed: 01/07/2023] Open
Abstract
UNLABELLED Avian leukosis virus subgroup J (ALV-J) is a simple retrovirus that can cause hemangiomas and myeloid tumors in chickens and is currently a major economic problem in Asia. Here we characterize ALV-J strain PDRC-59831, a newly studied U.S. isolate of ALV-J. Five-day-old chicken embryos were infected with this virus, and the chickens developed myeloid leukosis and hemangiomas within 2 months after hatching. To investigate the mechanism of pathogenesis, we employed high-throughput sequencing to analyze proviral integration sites in these tumors. We found expanded clones with integrations in the MET gene in two of the five hemangiomas studied. This integration locus was not seen in previous work characterizing ALV-J-induced myeloid leukosis. MET is a known proto-oncogene that acts through a diverse set of signaling pathways and is involved in many neoplasms. We show that tumors harboring MET integrations exhibit strong overexpression of MET mRNA. IMPORTANCE These data suggest that ALV-J induces oncogenesis by insertional mutagenesis, and integrations in the MET oncogene can drive the overexpression of MET and contribute to the development of hemangiomas.
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23
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Furlan A, Kherrouche Z, Montagne R, Copin MC, Tulasne D. Thirty Years of Research on Met Receptor to Move a Biomarker from Bench to Bedside. Cancer Res 2014; 74:6737-44. [DOI: 10.1158/0008-5472.can-14-1932] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Montagne R, Furlan A, Kherrouche Z, Tulasne D. [Thirty years of Met receptor research: from the discovery of an oncogene to the development of targeted therapies]. Med Sci (Paris) 2014; 30:864-73. [PMID: 25311021 DOI: 10.1051/medsci/20143010013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
In 1984, the Met receptor and its ligand, the HGF/SF, were discovered thanks to their ability to induce cell transformation and proliferation. Thirty years of research highlighted their crucial role in the development and homeostasis of various structures, including many epithelial organs. This period also allowed unraveling the structural basis of their interaction and their complex signaling network. In parallel, Met was shown to be deregulated and associated with a poor prognosis in many cancers. Met involvement in resistance to current therapies is also being deciphered. Based on these data, pharmaceutical companies developed a variety of Met inhibitors, some of which are evaluated in phase III clinical trials. In this review, we trace the exemplary track record of research on Met receptor, which allowed moving from bench to bedside through the development of therapies targeting its activity. Many questions still remain unanswered such as the involvement of Met in several processes of development, the mechanisms involving Met in resistance to current therapies or the likely emergence of resistances to Met-targeted therapies.
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Affiliation(s)
- Rémi Montagne
- CNRS UMR 8161, Institut de biologie de Lille, Institut Pasteur de Lille, université de Lille 1 et 2, SIRIC ONCOLille, IFR142, 1, rue du Professeur Calmette, 59021 Lille, France
| | - Alessandro Furlan
- CNRS UMR 8161, Institut de biologie de Lille, Institut Pasteur de Lille, université de Lille 1 et 2, SIRIC ONCOLille, IFR142, 1, rue du Professeur Calmette, 59021 Lille, France
| | - Zoulika Kherrouche
- CNRS UMR 8161, Institut de biologie de Lille, Institut Pasteur de Lille, université de Lille 1 et 2, SIRIC ONCOLille, IFR142, 1, rue du Professeur Calmette, 59021 Lille, France
| | - David Tulasne
- CNRS UMR 8161, Institut de biologie de Lille, Institut Pasteur de Lille, université de Lille 1 et 2, SIRIC ONCOLille, IFR142, 1, rue du Professeur Calmette, 59021 Lille, France
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25
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Zheng Q, Wu H, Cao J, Ye J. Hepatocyte growth factor activator inhibitor type‑1 in cancer: advances and perspectives (Review). Mol Med Rep 2014; 10:2779-85. [PMID: 25310042 DOI: 10.3892/mmr.2014.2628] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Accepted: 06/05/2014] [Indexed: 11/06/2022] Open
Abstract
Cancer is one of the most common diseases, with high morbidity and mortality rates. Large‑scale efforts have been made to understand the pathogenesis of the disease, particularly in the advanced stages, in order to develop effective therapeutic approaches. Hepatocyte growth factor activator inhibitor type-1 (HAI-1), also known as serine protease inhibitor Kunitz type 1, inhibits the activity of several trypsin-like serine proteases. In particular, HAI-1 suppresses hepatocyte growth factor (HGF) activator and matriptase, resulting in subsequent inhibition of HGF/scatter factor and macrophage‑stimulating protein (MSP). HGF and MSP are involved in cancer development and progression, via the receptors Met receptor tyrosine kinase (RTK) and Ron RTK, respectively. Therefore, HAI-1-mediated downregulation of HGF and MSP signaling may suppress tumorigenesis and progression in certain types of cancers. Abnormal HAI-1 expression levels have been observed in various types of human cancer. The exact function of HAI-1 in cancer pathogenesis, however, has not been fully elucidated. In this review, the focus is on the potential impact of aberrant HAI-1 expression levels on tumorigenesis and progression, the underlying mechanisms, and areas that require further investigation to clarify the precise role of HAI-1 in cancer.
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Affiliation(s)
- Qiaoli Zheng
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Haijian Wu
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Jiang Cao
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Jingjia Ye
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
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26
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Delitto D, Vertes-George E, Hughes SJ, Behrns KE, Trevino JG. c-Met signaling in the development of tumorigenesis and chemoresistance: Potential applications in pancreatic cancer. World J Gastroenterol 2014; 20:8458-8470. [PMID: 25024602 PMCID: PMC4093697 DOI: 10.3748/wjg.v20.i26.8458] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 12/18/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer deaths in the United States. The majority of patients are candidates only for palliative chemotherapy, which has proven largely ineffective in halting tumor progression. One proposed mechanism of chemoresistance involves signaling via the mesenchymal-epithelial transition factor protein (MET), a previously established pathway critical to cell proliferation and migration. Here, we review the literature to characterize the role of MET in the development of tumorigenesis, metastasis and chemoresistance, highlighting the potential of MET as a therapeutic target in pancreatic cancer. In this review, we characterize the role of c-Met in the development of tumorigenesis, metastasis and chemoresistance, highlighting the potential of c-Met as a therapeutic target in pancreatic cancer.
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MESH Headings
- Animals
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/enzymology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/secondary
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Drug Design
- Drug Resistance, Neoplasm/genetics
- Humans
- Molecular Targeted Therapy
- Neoplastic Stem Cells/enzymology
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/enzymology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/pathology
- Protein Kinase Inhibitors/therapeutic use
- Proto-Oncogene Proteins c-met/antagonists & inhibitors
- Proto-Oncogene Proteins c-met/genetics
- Proto-Oncogene Proteins c-met/metabolism
- Signal Transduction/drug effects
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27
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Jardim DLF, de Melo Gagliato D, Falchook G, Zinner R, Wheler JJ, Janku F, Subbiah V, Piha-Paul SA, Fu S, Tannir N, Corn P, Tang C, Hess K, Roy-Chowdhuri S, Kurzrock R, Meric-Bernstam F, Hong DS. MET abnormalities in patients with genitourinary malignancies and outcomes with c-MET inhibitors. Clin Genitourin Cancer 2014; 13:e19-26. [PMID: 25087088 DOI: 10.1016/j.clgc.2014.06.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Revised: 06/22/2014] [Accepted: 06/27/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND The purpose of this study was to determine the prevalence of MET amplification and mutation among GU malignancies and its association with clinical factors and responses to c-MET inhibitors. PATIENTS AND METHODS Patients with GU malignancies referred to our Phase I Clinical Trials Program were evaluated for MET mutation and amplification and outcomes using protocols with c-MET inhibitors. RESULTS MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial, and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 renal cell carcinoma [RCC] [1 clear cell and 1 papillary] and 1/16 prostate cancer). No demographic characteristics were associated with specific MET abnormalities, but patients who tested positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild type MET). Median overall survival after phase I consultation was 6.1 and 11.5 months for patients with and without a MET alteration, respectively (hazard ratio, 2.8; 95% confidence interval, 1.1 to 6.9; P = .034). Twenty-nine (25%) patients were treated according to a c-MET inhibitor protocol. Six (21%) had a partial response (prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (range, 0.4-19.7) for all treated patients with no responses in patients with a MET abnormality or single-agent c-MET inhibitor treatment. CONCLUSION MET genetic abnormalities occur in diverse GU malignancies and are associated with a worse prognosis in a phase I setting. Efficacy of c-MET inhibitors was more pronounced in patients without MET abnormalities and when combined with other targets/drugs.
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Affiliation(s)
- Denis L F Jardim
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
| | - Débora de Melo Gagliato
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Gerald Falchook
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Ralph Zinner
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Jennifer J Wheler
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Filip Janku
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Sarina A Piha-Paul
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Nizar Tannir
- Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Paul Corn
- Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Chad Tang
- Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Kenneth Hess
- Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Sinchita Roy-Chowdhuri
- Department of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Razelle Kurzrock
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - David S Hong
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas M.D. Anderson Cancer Center, Houston, TX
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28
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Analysis of MET genetic aberrations in patients with breast cancer at MD Anderson Phase I unit. Clin Breast Cancer 2014; 14:468-74. [PMID: 25065564 DOI: 10.1016/j.clbc.2014.06.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 06/04/2014] [Accepted: 06/17/2014] [Indexed: 11/22/2022]
Abstract
BACKGROUND c-MET is a receptor tyrosine kinase whose phosphorylation activates important proliferation pathways. MET amplification and mutation have been described in various malignancies, including breast cancer (BC), and c-MET overexpression is associated with worse survival outcomes in patients with BC. We describe MET mutation and amplification rates in a BC cohort of patients referred to a Phase I Unit. METHODS We reviewed the electronic medical records of all patients with advanced BC tested for MET amplification, mutation, or both who were referred to the Department of Investigational Cancer Therapeutics at MD Anderson. RESULTS A total of 107 patients with advanced BC were analyzed for MET mutation/variant (88 patients) or amplification (63 patients). Of these, 49 were tested for both genetic abnormalities. Three of 63 patients (4.7%) demonstrated MET gene amplification by fluorescence in situ hybridization (2 in primary tissue; 1 in metastatic site). MET mutation/variant was detected in 8 of 88 patients (9%). High-grade tumors were characteristic of all patients harboring MET amplification and were present in 7 of 8 (87.5%) of those with MET mutation. Metastatic sites were greater in MET-amplified compared with wild-type patients (median of 7 vs. 3 sites). Five of 8 patients (62.5%) with MET mutations had triple negative BC compared with 46% in controls. In addition, patients with positive test results for MET aberrations (n = 11) had inferior overall survival (OS) from Phase I consult compared with wild-type patients (n = 37), although this was not statistically significant (median OS = 9 vs. 15 months, P = .43). CONCLUSIONS In this cohort of patients with BC who were referred to our Phase I Department, MET aberrations were associated with higher metastatic burden and high-grade histology. We could not demonstrate differences in survival outcomes because of a small sample size.
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29
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Mai A, Muharram G, Barrow-McGee R, Baghirov H, Rantala J, Kermorgant S, Ivaska J. Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1. J Cell Sci 2014; 127:1938-52. [DOI: 10.1242/jcs.140657] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
ABSTRACT
Many carcinomas have acquired oncogenic mechanisms for activating c-Met, including c-Met overexpression and excessive autocrine or paracrine stimulation with hepatocyte growth factor (HGF). However, the biological outcome of c-Met activation through these distinct modes remains ambiguous. Here, we report that HGF-mediated c-Met stimulation triggers a mesenchymal-type collective cell invasion. By contrast, the overexpression of c-Met promotes cell rounding. Moreover, in a high-throughput siRNA screen that was performed using a library of siRNAs against putative regulators of integrin activity, we identified RhoA and the clathrin-adapter protein HIP1 as crucial c-Met effectors in these morphological changes. Transient RhoA activation was necessary for the HGF-induced invasion, whereas sustained RhoA activity regulated c-Met-induced cell rounding. In addition, c-Met-induced cell rounding correlated with the phosphorylation of filamin A and the downregulation of active cell-surface integrins. By contrast, a HIP1-mediated increase in β1-integrin turnover was required for the invasion triggered by HGF. Taken together, our results indicate that c-Met induces distinct cell morphology alterations depending on the stimulus that activates c-Met.
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Affiliation(s)
- Anja Mai
- Turku Centre for Biotechnology, University of Turku, Turku 20521, Finland
- VTT Technical Research Centre of Finland, Medical Biotechnology, Turku 20520, Finland
- Department of Biochemistry and Food Chemistry, University of Turku, Turku 20521, Finland
| | - Ghaffar Muharram
- Turku Centre for Biotechnology, University of Turku, Turku 20521, Finland
- VTT Technical Research Centre of Finland, Medical Biotechnology, Turku 20520, Finland
| | - Rachel Barrow-McGee
- Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Habib Baghirov
- Turku Centre for Biotechnology, University of Turku, Turku 20521, Finland
- VTT Technical Research Centre of Finland, Medical Biotechnology, Turku 20520, Finland
| | - Juha Rantala
- VTT Technical Research Centre of Finland, Medical Biotechnology, Turku 20520, Finland
| | - Stéphanie Kermorgant
- Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
| | - Johanna Ivaska
- Turku Centre for Biotechnology, University of Turku, Turku 20521, Finland
- VTT Technical Research Centre of Finland, Medical Biotechnology, Turku 20520, Finland
- Department of Biochemistry and Food Chemistry, University of Turku, Turku 20521, Finland
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30
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Koeppen H, Rost S, Yauch RL. Developing biomarkers to predict benefit from HGF/MET pathway inhibitors. J Pathol 2014; 232:210-8. [PMID: 24105670 DOI: 10.1002/path.4268] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 09/11/2013] [Accepted: 09/15/2013] [Indexed: 12/13/2022]
Abstract
Activation of the MET signalling pathway is critical in regulating multiple cellular processes underlying tumourigenic growth and has represented an attractive target for therapeutic intervention in cancer. Early stage clinical studies of multiple agents targeting this pathway have been undertaken, frequently in unselected patient cohorts with variable results. Promising data in patient subgroups in these studies indicate the need for predictive biomarkers to identify the patients most likely to benefit from these therapies. In this review, we discuss the current knowledge of mechanisms of MET activation, the status of the clinical evaluation of MET-targeted therapies, the associated efforts to identify and validate biomarkers, and the considerations and challenges for potential development of companion diagnostics.
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Affiliation(s)
- Hartmut Koeppen
- Department of Research Pathology, Genentech, Inc, South San Francisco, CA, USA
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31
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Maroun CR, Rowlands T. The Met receptor tyrosine kinase: a key player in oncogenesis and drug resistance. Pharmacol Ther 2013; 142:316-38. [PMID: 24384534 DOI: 10.1016/j.pharmthera.2013.12.014] [Citation(s) in RCA: 164] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 12/12/2013] [Indexed: 12/14/2022]
Abstract
The Met receptor tyrosine kinase (RTK) is an attractive oncology therapeutic target. Met and its ligand, HGF, play a central role in signaling pathways that are exploited during the oncogenic process, including regulation of cell proliferation, invasion, angiogenesis, and cancer stem cell regulation. Elevated Met and HGF as well as numerous Met genetic alterations have been reported in human cancers and correlate with poor outcome. Alterations of pathways that regulate Met, such as the ubiquitin ligase c-Cbl are also likely to activate Met in the oncogenic setting. Moreover, interactive crosstalk between Met and other receptors such as EGFR, HER2 and VEGFR, underlies a key role for Met in resistance to other RTK-targeted therapies. A large body of preclinical and clinical data exists that supports the use of either antibodies or small molecule inhibitors that target Met or HGF as oncology therapeutics. The prognostic potential of Met expression has been suggested from studies in numerous cancers including lung, renal, liver, head and neck, stomach, and breast. Clinical trials using Met inhibitors indicate that the level of Met expression is a determinant of trial outcome, a finding that is actively under investigation in multiple clinical scenarios. Research in Met prognostics and predictors of drug response is now shifting toward more sophisticated methodologies suitable for development as validated and effective biomarkers that can be partnered with therapeutics to improve patient survival.
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Affiliation(s)
- Christiane R Maroun
- Mirati Therapeutics, 7150 Frederick-Banting, Suite 200, Montreal, Quebec H4S 2A1, Canada.
| | - Tracey Rowlands
- Mirati Therapeutics, 7150 Frederick-Banting, Suite 200, Montreal, Quebec H4S 2A1, Canada
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32
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Shin JS, Hong SW, Moon JH, Kim JS, Jung KA, Kim SM, Lee DH, Kim I, Yoon SJ, Lee CG, Choi EK, Lee JY, Kim KP, Hong YS, Lee JL, Kim B, Choi EK, Lee JS, Jin DH, Kim TW. NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants. Invest New Drugs 2013; 32:389-99. [DOI: 10.1007/s10637-013-0039-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 10/08/2013] [Indexed: 12/01/2022]
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33
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Yang OC, Maxwell PH, Pollard PJ. Renal cell carcinoma: translational aspects of metabolism and therapeutic consequences. Kidney Int 2013; 84:667-81. [DOI: 10.1038/ki.2013.245] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2013] [Revised: 03/12/2013] [Accepted: 03/14/2013] [Indexed: 02/08/2023]
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34
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Medová M, Pochon B, Streit B, Blank-Liss W, Francica P, Stroka D, Keogh A, Aebersold DM, Blaukat A, Bladt F, Zimmer Y. The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants. Mol Cancer Ther 2013; 12:2415-24. [PMID: 24061647 DOI: 10.1158/1535-7163.mct-13-0151] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The receptor tyrosine kinase MET is a prime target in clinical oncology due to its aberrant activation and involvement in the pathogenesis of a broad spectrum of malignancies. Similar to other targeted kinases, primary and secondary mutations seem to represent an important resistance mechanism to MET inhibitors. Here, we report the biologic activity of a novel MET inhibitor, EMD1214063, on cells that ectopically express the mutated MET variants M1268T, Y1248H, H1112Y, L1213V, H1112L, V1110I, V1206L, and V1238I. Our results show a dose-dependent decrease in MET autophosphorylation in response to EMD1214063 in five of the eight cell lines (IC50 2-43 nmol/L). Blockade of MET by EMD1214063 was accompanied by a reduced activation of downstream effectors in cells expressing EMD1214063-sensitive mutants. In all sensitive mutant-expressing lines, EMD1214063 altered cell-cycle distribution, primarily with an increase in G1 phase. EMD1214063 strongly influenced MET-driven biologic functions, such as cellular morphology, MET-dependent cell motility, and anchorage-independent growth. To assess the in vivo efficacy of EMD1214063, we used a xenograft tumor model in immunocompromised mice bearing NIH3T3 cells expressing sensitive and resistant MET-mutated variants. Animals were randomized for the treatment with EMD1214063 (50 mg/kg/d) or vehicle only. Remarkably, five days of EMD1214063 treatment resulted in a complete regression of the sensitive H1112L-derived tumors, whereas tumor growth remained unaffected in mice with L1213V tumors and in vehicle-treated animals. Collectively, the current data identifies EMD1214063 as a potent MET small-molecule inhibitor with selective activity towards mutated MET variants.
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Affiliation(s)
- Michaela Medová
- Corresponding Author: Michaela Medová, Radiation Oncology, Department of Clinical Research, University of Bern/Inselspital, MEM-E815, Murtenstrassse 35, 3010 Bern, Switzerland.
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35
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Graveel CR, Tolbert D, Vande Woude GF. MET: a critical player in tumorigenesis and therapeutic target. Cold Spring Harb Perspect Biol 2013; 5:a009209. [PMID: 23818496 PMCID: PMC3685898 DOI: 10.1101/cshperspect.a009209] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Since its discovery more than 25 years ago, numerous studies have established that the MET receptor is unique among tyrosine kinases. Signaling through MET is necessary for normal development and for the progression of a wide range of human cancers. MET activation has been shown to drive numerous signaling pathways; however, it is not clear how MET signaling mediates diverse cellular responses such as motility, invasion, growth, and angiogenesis. Great strides have been made in understanding the pleotropic aspects of MET signaling using three-dimensional molecular structures, cell culture systems, human tumors, and animal models. These combined approaches have driven the development of MET-targeted therapeutics that have shown promising results in the clinic. Here we examine the unique features of MET and hepatocyte growth factor/scatter factor (HGF/SF) structure and signaling, mutational activation, genetic mouse models of MET and HGF/SF, and MET-targeted therapeutics.
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Affiliation(s)
- Carrie R Graveel
- Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
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36
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Andersen NJ, Nickoloff BJ, Dykema KJ, Boguslawski EA, Krivochenitser RI, Froman RE, Dawes MJ, Baker LH, Thomas DG, Kamstock DA, Kitchell BE, Furge KA, Duesbery NS. Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma. Mol Cancer Ther 2013; 12:1701-14. [PMID: 23804705 DOI: 10.1158/1535-7163.mct-12-0893] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Angiosarcoma is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human angiosarcoma, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive extracellular signal-regulated kinase (ERK) activation. The mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multireceptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human angiosarcoma, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was upregulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human angiosarcoma. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human angiosarcoma, and it highlights the use of spontaneous canine cancers as a model of human disease.
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Affiliation(s)
- Nicholas J Andersen
- Corresponding Author: Nicholas S. Duesbery, Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, 333 Bostwick Ave., NE, Grand Rapids, MI 49503.
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Abstract
a substantial proportion of non-small-cell lung cancer (NSCLC), and adenocarcinoma in particular, depends on a so-called 'driver mutation' for their malignant phenotype. This genetic alteration induces and sustains tumorigenesis, and targeting of its protein product can result in growth inhibition, tumor response and increased patient survival. NSCLC can thus be subdivided into clinically relevant molecular subsets. Mutations in EGFR best illustrate the therapeutic relevance of molecular classification. This article reviews the scope of presently known driving molecular alterations, including ROS1, BRAF, KRAS, HER2 and PIK3CA, with a special emphasis on aLK rearrangements, and outlines their potential therapeutic applications.
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Affiliation(s)
- S Zimmermann
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland
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38
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Scagliotti GV, Novello S, von Pawel J. The emerging role of MET/HGF inhibitors in oncology. Cancer Treat Rev 2013; 39:793-801. [PMID: 23453860 DOI: 10.1016/j.ctrv.2013.02.001] [Citation(s) in RCA: 154] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 01/31/2013] [Accepted: 02/02/2013] [Indexed: 02/06/2023]
Abstract
The N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (MET) receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) control cellular signaling cascades that direct cell growth, proliferation, survival, and motility. Aberrant MET/HGF activation has been observed in many tumor types, can occur by multiple mechanisms, and promotes cellular proliferation and metastasis via growth factor receptors and other oncogenic receptor pathways. Thus, MET/HGF inhibition has emerged as targeted anticancer therapies. Preclinically, neoplastic and metastatic phenotypes of several tumor cells, including non-small cell lung cancer, hepatocellular carcinoma, and gastric cancer, were abrogated by MET inhibition. Ongoing clinical development with tivantinib, cabozantinib, onartuzumab, crizotinib, rilotumumab, and ficlatuzumab has shown encouraging results. These trials have established a key role for MET in a variety of tumor types. Evidence is emerging for identification of aberrant MET activity biomarkers and selection of patient subpopulations that may benefit from targeted MET and HGF inhibitor treatment.
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High MET expression is an adverse prognostic factor in patients with triple-negative breast cancer. Br J Cancer 2013; 108:1100-5. [PMID: 23422757 PMCID: PMC3619063 DOI: 10.1038/bjc.2013.31] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background: The mesenchymal–epithelial transition (MET) pathway is frequently altered in tumours. The purpose of our study was to determine the prognostic value of tumour MET expression levels in patients with triple-negative breast cancer (TNBC), in order to strengthen the rationale for targeted therapy of TNBC using MET inhibitors. Methods: We determined expression of MET in formalin-fixed paraffin-embedded surgical specimens of TNBC by immunohistochemistry. Recurrence-free and overall survival was analysed with Cox models adjusted for clinical and pathological factors. Results: Immunostaining for MET was classified as high in 89 of 170 (52%) tumours. MET expression was more frequently observed in G3 carcinomas (P=0.02) but was not significantly associated to any of the other clinical or pathological parameters. High MET expression predicted shorter survival of the patients. Multivariate Cox proportional hazards regression analyses identified MET to be an independent prognostic factor for recurrence (adjusted hazard ratio (HR) for recurrence 3.43; 95% confidence interval (CI) 1.65–7.12; P=0.001) and death (adjusted HR for death 3.74; 95% CI 1.65–8.46; P=0.002). Conclusion: These results provide further evidence that the MET pathway could be exploited as a target for TNBC.
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Blumenschein GR, Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol 2012; 30:3287-96. [PMID: 22869872 DOI: 10.1200/jco.2011.40.3774] [Citation(s) in RCA: 224] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The hepatocyte growth factor (HGF) and its receptor, the transmembrane tyrosine kinase cMET, promote cell proliferation, survival, motility, and invasion as well as morphogenic changes that stimulate tissue repair and regeneration in normal cells but can be co-opted during tumor growth. MET overexpression, with or without gene amplification, has been reported in a variety of human cancers, including breast, lung, and GI malignancies. Furthermore, high levels of HGF and/or cMET correlate with poor prognosis in several tumor types, including breast, ovarian, cervical, gastric, head and neck, and non-small-cell lung cancers. Gene amplification and protein overexpression of cMET drive resistance to epidermal growth factor receptor family inhibitors, both in preclinical models and in patients. It is increasingly apparent that the HGF-cMET axis signaling network is complex, and rational combinatorial therapy is needed for optimal clinical efficacy. Better understanding of HGF-cMET axis signaling and the mechanism of action of HGF-cMET inhibitors, along with the identification of biomarkers of response and resistance, will lead to more effective targeting of this pathway for cancer therapy.
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Affiliation(s)
- George R Blumenschein
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX 77030-4009, USA.
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Liu Y, Yang Y, Ye YC, Shi QF, Chai K, Tashiro SI, Onodera S, Ikejima T. Activation of ERK-p53 and ERK-mediated phosphorylation of Bcl-2 are involved in autophagic cell death induced by the c-Met inhibitor SU11274 in human lung cancer A549 cells. J Pharmacol Sci 2012; 118:423-32. [PMID: 22466960 DOI: 10.1254/jphs.11181fp] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
Abstract
SU11274, a small molecule inhibitor of c-Met, was reported to induce apoptosis in human non-small-cell lung cancer (NSCLC) cells. However, SU11274-mediated autophagy in NSCLC cells has rarely been reported. The aim of this study was to elucidate the molecular mechanisms mediating SU11274-induced autophagy in NSCLC A549 cells. Here we reported that SU11274-induced autophagy was accompanied with an increase in the conversion of LC3-I to LC3-II and up-regulation of Beclin-1 expression. Subsequently, we also found that small interfering RNA against c-Met induced A549 cell autophagy while promotion of c-Met by hepatocyte growth factor (HGF) suppressed A549 cell autophagy. Inhibition of autophagy by 3-methyladenine (3-MA) suppressed SU11274-induced cell death, suggesting that SU11274-induced autophagy caused cell death. Further study showed that ERK and p53 were activated after SU11274 treatment. Interruption of ERK and p53 activities decreased SU11274-induced autophagy, and blocking of ERK by the specific inhibitor PD98059 suppressed SU11274-induced p53 activation. Moreover, ERK activation upregulated Beclin-1 expression through induction of Bcl-2 phosphorylation, but p53 did not induce Bcl-2 phosphorylation. In conclusion, inhibition of c-Met induced autophagic cell death, which was associated with ERK-p53 activation and ERK-mediated Bcl-2 phosphorylation in A549 cells.
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Affiliation(s)
- Ying Liu
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, PR China
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Onvani S, Terakawa Y, Smith C, Northcott P, Taylor M, Rutka J. Molecular genetic analysis of the hepatocyte growth factor/MET signaling pathway in pediatric medulloblastoma. Genes Chromosomes Cancer 2012; 51:675-88. [PMID: 22447520 DOI: 10.1002/gcc.21954] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Revised: 02/15/2012] [Accepted: 02/20/2012] [Indexed: 01/24/2023] Open
Abstract
The hepatocyte growth factor (HGF)/MET pathway plays a critical role in the development of the nervous system and has been implicated in medulloblastoma pathogenesis. Recent studies have shown a role for gene amplification of activators of this pathway, as well as silencing of its inhibitors in medulloblastoma pathogenesis. We analyzed exon array data from a cohort of 103 primary medulloblastomas to show that HGF/MET pathway elements are dysregulated in tumors compared to normal cerebellum. To determine if mutation of HGF/MET pathway genes is a mechanism for pathway dysregulation, we conducted a mutational analysis by exon resequencing of three key components of this pathway, including serine protease inhibitor Kunitz-type 1 (SPINT1), serine protease inhibitor Kunitz-type 2 (SPINT2), and MET, in 32 primary human medulloblastoma specimens. From this analysis, we identified multiple coding synonymous and nonsynonymous single nucleotide polymorphisms in these genes among the 32 tumor samples. Interestingly, we also discovered two unreported sequence variants in SPINT1 and SPINT2 in two tumors that resulted in Arginine to Histidine amino acid substitutions at codons 418 and 233, respectively. However, conservation assessment and functional assays of these two variants indicate that they involve nonconserved residues and that they do not affect the function of SPINT1 and SPINT2 as tumor suppressor genes. In conclusion, our data suggest that mutation alone plays a minor role in causing aberrancies of the HGF/MET pathway in medulloblastoma in comparison with other malignancies such as breast, hepatocellular, renal, and lung carcinomas.
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Affiliation(s)
- Sara Onvani
- Arthur and Sonia Labatt Brain Tumour Research Centre, Department of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
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Abstract
Uncontrolled cell survival, growth, angiogenesis and metastasis are essential hallmarks of cancer. Genetic and biochemical data have demonstrated that the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the tyrosine kinase MET, have a causal role in all of these processes, thus providing a strong rationale for targeting these molecules in cancer. Parallel progress in understanding the structure and function of HGF/SF, MET and associated signalling components has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors. In this Review, we discuss these advances, as well as results from recent clinical studies that demonstrate that inhibiting MET signalling in several types of solid human tumours has major therapeutic value.
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Affiliation(s)
- Ermanno Gherardi
- Medical Research Council (MRC) Centre, Hills Road, Cambridge CB2 2QH, UK.
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Liu X, Wang Q, Yang G, Marando C, Koblish HK, Hall LM, Fridman JS, Behshad E, Wynn R, Li Y, Boer J, Diamond S, He C, Xu M, Zhuo J, Yao W, Newton RC, Scherle PA. A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin Cancer Res 2011; 17:7127-38. [PMID: 21918175 DOI: 10.1158/1078-0432.ccr-11-1157] [Citation(s) in RCA: 188] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
PURPOSE The c-MET receptor tyrosine kinase plays important roles in the formation, progression, and dissemination of human cancer and presents an attractive therapeutic target. This study describes the preclinical characterization of INCB28060, a novel inhibitor of c-MET kinase. EXPERIMENTAL DESIGN Studies were conducted using a series of in vitro and in vivo biochemical and biological experiments. RESULTS INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers. CONCLUSIONS Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment.
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Affiliation(s)
- Xiangdong Liu
- Incyte Corporation, Wilmington, Delaware 19880, USA.
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Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood 2011; 118:3613-21. [PMID: 21813452 DOI: 10.1182/blood-2010-06-289207] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD)-induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent.
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Abstract
INTRODUCTION The aberrantly upregulated c-mesenchymal-epithelia transition factor (c-MET) signaling pathway has been considered to be an attractive target for cancer intervention owing to the important roles it plays in tumor formation, progression, metastasis, angiogenesis and drug resistance. Based on the historical preclinical evidence, a number of c-MET pathway targeted agents are being developed in the clinic, and recent clinical data have begun to provide some insight into which tumor types and patient populations a c-MET pathway inhibitor may be beneficial for. AREAS COVERED Through reviewing recent publications in the literature and information disclosed in other public forums, we describe the current understanding of c-MET biology in human malignancies and discuss the latest progress in the development of c-MET pathway inhibitors for cancer treatment. EXPERT OPINION The c-MET pathway inhibitors currently being evaluated in the clinic have demonstrated compelling evidence of clinical activity in different cancer types and may provide significant therapeutic opportunities. The challenges, however, are to identify the tumor types and patient populations that benefit most, and find the most effective combinations of therapies while minimizing potential toxicity.
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Affiliation(s)
- Xiangdong Liu
- Incyte Corporation, Experimental Station, Wilmington, DE 19880, USA.
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Stella GM, Benvenuti S, Gramaglia D, Scarpa A, Tomezzoli A, Cassoni P, Senetta R, Venesio T, Pozzi E, Bardelli A, Comoglio PM. MET mutations in cancers of unknown primary origin (CUPs). Hum Mutat 2010; 32:44-50. [DOI: 10.1002/humu.21374] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Accepted: 09/13/2010] [Indexed: 12/12/2022]
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Graveel CR, DeGroot JD, Sigler RE, Vande Woude GF. Germline met mutations in mice reveal mutation- and background-associated differences in tumor profiles. PLoS One 2010; 5:e13586. [PMID: 21049054 PMCID: PMC2963642 DOI: 10.1371/journal.pone.0013586] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 09/24/2010] [Indexed: 12/14/2022] Open
Abstract
Background The receptor tyrosine kinase Met is involved in the progression and metastasis of numerous human cancers. Although overexpression and autocrine activation of the Met signaling pathway are commonly found in human cancers, mutational activation of Met has been observed in small cell and non-small cell lung cancers, lung adenocarcinomas, renal carcinomas, and mesotheliomas. Methodology/Principal Findings To investigate the influence of mutationally activated Met in tumorigenesis, we utilized a novel mouse model. Previously, we observed that various Met mutations developed unique mutation-specific tumor spectra on a C57BL/6 background. Here, we assessed the effect of genetic background on the tumorigenic potential of mutationally activated Met. For this purpose, we created congenic knock-in lines of the Met mutations D1226N, M1248T, and Y1228C on the FVB/N background. Consistent with the mutation-specific tumor spectra, several of the mutations were associated with the same tumor types as observed on C57BL/6 background. However, on the FVB/N background most developed a high incidence of mammary carcinomas with diverse histopathologies. Conclusions/Significance This study demonstrates that on two distinct mouse backgrounds, Met is able to initiate tumorigenesis in multiple cell types, including epithelial, hematopoietic, and endothelial. Furthermore, these observations emphasize that even a modest increase in Met activation can initiate tumorigenesis with both the Met mutational spectra and host background having profound influence on the type of tumor generated. Greater insight into the interaction of genetic modifiers and Met signaling will significantly enhance our ability to tailor combination therapies for Met-driven cancers.
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Affiliation(s)
- Carrie R Graveel
- Department of Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
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Cañadas I, Rojo F, Arumí-Uría M, Rovira A, Albanell J, Arriola E. C-MET as a new therapeutic target for the development of novel anticancer drugs. Clin Transl Oncol 2010; 12:253-60. [PMID: 20462834 DOI: 10.1007/s12094-010-0501-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
MET is a tyrosine kinase receptor that, upon binding of its natural ligand, the hepatocyte growth factor (HGF), is phosphorylated and subsequently activates different signalling pathways involved in proliferation, motility, migration and invasion. MET has been found to be aberrantly activated in human cancer via mutation, amplification or protein overexpression. MET expression and activation have been associated with prognosis in a number of tumour types and predict response to MET inhibitors in preclinical models. Here we review the HGF/MET signalling pathway, its role in human cancer and the different inhibitory strategies that have been developed for therapeutic use.
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Affiliation(s)
- I Cañadas
- Molecular Therapeutics and Biomarkers in Cancer Laboratory, Institut Municipal d'Investigacions Mediques, Hospital del Mar, Barcelona, Spain
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Nam HJ, Chae S, Jang SH, Cho H, Lee JH. The PI3K-Akt mediates oncogenic Met-induced centrosome amplification and chromosome instability. Carcinogenesis 2010; 31:1531-40. [PMID: 20584748 DOI: 10.1093/carcin/bgq133] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The oncogenic ability of aberrant hepatocyte growth factor receptor (Met) signaling is thought to mainly rely on its mitogenic and anti-apoptotic effects. Recently, however, cumulating evidences suggest that genomic instability may be a crucial factor in tumorigenesis. Here, we address whether oncogenic Met receptor is linked to the centrosome abnormality and genomic instability. We showed that expression of the constitutive active Met (CA-Met) induced supernumerary centrosomes probably due to deregulated centrosome duplication, which was accompanied with multipolar spindle formation and aneuploidy. Interestingly, LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly suppressed the appearance of supernumerary centrosomes. Moreover, knockdown of Akt with small interfering RNAs and overexpression of phosphatase and tensin homolog or dominant-negative Akt abrogated supernumerary centrosome formation, evidencing the involvement of PI3K signaling. We further showed that expression of CA-Met significantly increased aneuploidy in p53(-/-) HCT116 cells, but not in p53(+/+) HCT116 cells, indicating that the ability of CA-Met to induce chromosomal instability (CIN) phenotype is related with p53 status. Together, our data demonstrate that aberrant hepatocyte growth factor/Met signaling induces centrosome amplification and CIN via the PI3K-Akt pathway, providing an example that oncogenic growth factor signals prevalent in a wide variety of cancers have cross talks to centrosome abnormality and CIN.
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Affiliation(s)
- Hyun-Ja Nam
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea
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