Fax +49 761 4 52 07 14 Information@Karger.com www.karger.com Accessible online at: www.karger.com/ort Original Article Oncol Res Treat 2017;40:198–202 DOI: 10.1159/000457801 MET Amplification and Response to MET Inhibitors in Stage IV Lung Adenocarcinoma Moushumi Suryavanshi a Aekta Shah b Dushyant Kumar a Manoj K. Panigrahi a Anurag Metha c Ullas Batra d a Centre for Molecular Diagnostic and Cell Biology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India; b Histopathology Department , Tata Medical Centre, Kolkata, India; c Medical Oncology Department, Rajiv Gandhi Cancer Institute and research Centre, New Delhi, India; d Lab Services, Rajiv Gandhi Cancer Institute and research Centre, New Delhi, India Introduction Lung cancer represents one of the leading causes of cancer-re- lated mortality worldwide. Recently, there has been a paradigm shift in the companion diagnostics and treatment of lung cancer. These advances have led to a new era of translational research, bringing targeted and personalized treatment into clinical practice. The oncological communities are now demanding biomarker anal- ysis to give the benefits of targeted therapy to more and more pa- tients for whom palliation was once the only option [1, 2]. This is especially true for actionable driver mutations and rearrangements like those of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, c-MET, BRAF, human epidermal growth factor receptor 2 (HER2) and RET [3–5]. c-MET gene amplification and overexpression in non-small-cell lung cancer (NSCLC) cell lines was first shown by Lutterbach et al. [6] in 2007. Like all tyrosine kinase (TK) receptors, c-MET is com- prised of a juxta-membrane, transmembrane and extracellular do- main. On ligand binding, phosphorylation of the docking site oc- curs, leading to stimulation of downstream pathways and causing increased cell growth, angiogenesis, migration, and survival [7, 8]. The prevalence of high c-MET copy number gain and amplifica- tion has ranged from 2.1% to 20.8% in various studies and been shown to be associated with bad prognosis [9–13]. c-MET protein expression, on the other hand, is 22.2–74.6% which is a little higher in NSCLC, and this too is associated with poor prognosis [14, 15]. c-MET amplification is also known as a mechanism of resistance after EGFR-TK inhibitor (TKI) therapy in about 20% of EGFR- positive lung tumors. Crizotinib has been shown to be an effective agent against c-MET signaling both in vivo and vitro [16–19]. Fluorescence in situ hybridization (FISH) is considered the most widely employed technique to look for c-MET amplification. How- ever, interpretation of the results may have technical difficulties due Keywords MET · Tyrosine kinase inhibitor (TKI) · ROS · Epidermal growth factor receptor (EGFR) · Crizotinib Summary Background: Non-small-cell lung cancers with MET am- plification may respond to c-MET inhibitors. Methods: We examined lung adenocarcinoma patients for muta- tions and amplification status of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS, MET. The clinical characteristics of patients with MET amplification and their responses to MET inhibitor therapy were studied. Results: Of the 76 patients ana- lyzed, 5 were positive for c-MET gene amplification and 4 cases showed an intermediate result. For 12 patients who were EGFR positive, a c-MET analysis on secondary biopsy tissue was performed following disease progres- sion. All 5 c-MET-positive patients were men. The age range in the study was 34–83 years. 4 of the 5 patients were started on crizotinib. 2 of these cases were positive following tyrosine kinase inhibitor therapy. 3 patients showed a response. 1 patient showed no response and was later found to have a concurrent T790M mutation. Conclusions: There are 2 categories of MET gene ampli- fication in lung cancer patients, de novo and that sec- ondary to TKI therapy. These patients can benefit from MET inhibitor therapy. Dual mechanisms of resistance, EGFR T790M mutation and c-MET amplification after TKI therapy, may suggest a poor prognosis. © 2017 S. Karger GmbH, Freiburg Received: November 10, 2016 Accepted: January 23, 2017 Published online: March 08, 2017 Dr. Moushumi Suryavanshi Centre for Molecular Diagnostic and Cell Biology Rajiv Gandhi Cancer Institute and Research Centre Rohini, New Delhi 110085, India moushumisuryavanshi @ gmail.com, suryavanshi.moushumi @ rgcirc.org © 2017 S. Karger GmbH, Freiburg