Background: Non-small-cell lung cancers with MET amplification may respond to c-MET inhibitors. Methods: We examined lung adenocarcinoma patients for mutations 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 analyzed, 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 progression. 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 amplification in lung cancer patients, de novo and that secondary 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.

Keedy VL, Temin S, Somerfield MR, et al.: American Society of Clinical Oncology provisional clinical opinion: Epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol 2011;29:2121-2127.
Pirker R, Herth FJ, Kerr KM, et al.: Consensus for EGFR mutation testing in non-small cell lung cancer: Results from a European workshop. J Thorac Oncol 2010;5:1706-1713.
Gandara DR, Li T, Lara PN Jr, et al.: Algorithm for codevelopment of new drug-predictive biomarker combinations: Accounting for inter- and intrapatient tumor heterogeneity. Clin Lung Cancer 2012;13:321-325.
Haber DA, Gray NS, Baselga J: The evolving war on cancer. Cell 2011;145:19-24.
Peters S, Adjei AA, Gridelli C, et al.: Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23:7:56-64.
Lutterbach B, Zeng Q, Davis LJ, et al.: Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res 2007;67:2081-2088.
Giordano S, Ponzetto C, Di Renzo DF, et al.: Tyrosine kinase receptor indistinguishable from the c-met protein. Nature 1989;339:155-156.
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF: Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003;4:915-925.
Cappuzzo F, Marchetti A, Skokan M, et al.: Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 2009;27:1667-1674.
Go H, Jeon YK, Park HJ, et al.: High MET gene copy number leads to shorter survival in patients with non-small cell lung cancer. J Thorac Oncol 2010;5:305-313.
Beau-Faller M, Ruppert AM, Voegeli AC, et al.: MET gene copy number in non-small cell lung cancer: Molecular analysis in a targeted tyrosine kinase inhibitor naive cohort. J Thorac Oncol 2008;3:331-339.
Chen YT, Chang JW, Liu HP, et al.: Clinical implications of high MET gene dosage in non-small cell lung cancer patients without previous tyrosine kinase inhibitor treatment. J Thorac Oncol 2011;6:2027-2035.
Dziadziuszko R, Wynes MW, Singh S, et al.: Correlation between MET gene copy number by silver in situ hybridization and protein expression by immunohistochemistry in non-small cell lung cancer. J Thorac Oncol 2012;7:340-347.
Onitsuka T, Uramoto H, Ono K, et al.: Comprehensive molecular analyses of lung adenocarcinoma with regard to the epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status. J Thorac Oncol 2010;5:591-596.
Sun W, Song L, Ai T, et al.: Prognostic value of MET, cyclin D1 and MET gene copy number in non-small cell lung cancer. J Biomed Res 2013;27:220-230.
Bean J, Brennan C, Shih JY, et al.: MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 2007;104:20932-20937.
Zou HY, Li Q, Lee JH, et al.: An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 2007;67:4408-4417.
Cappuzzo F, Hirsch FR, Rossi E, et al.: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643-655.
Tong JH, Yeung SF, Chan AW, et al.: MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin Cancer Res 2016;22:3048-3056.
Turke AB, Zejnullahu K, Wu YL, et al.: Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010;17:77-88.
Engelman JA, Zejnullahu K, Mitsudomi T, et al.: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-1043.
Pao W, Chmielecki J: Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010;10:760-774.
Azuma K, Yoshioka H, Yamamoto N, et al.: Tivantinib plus erlotinib versus placebo plus erlotinib in Asian patients with previously treated non-squamous NSCLC with wild-type EGFR: First report of a phase III ATTENTION trial. J Clin Oncol 2014;(suppl; abstr 8044).
Scagliotti G, Novello S, Ramlau R, et al.: MARQUEE: A randomized, double-blind, placebo-controlled, phase 3 trial of tivantinib (ARQ 197) plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, non-squamous, non-small-cell lung cancer (NSCLC). European Cancer Congress 2013;(Abstract E17-1821).
Toyokawa G, Seto T, Takenoyama M, Ichinose Y: Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary? Cancer Metastasis Rev 2015;34:797-805.
Gou LY, Li AN, Yang JJ, et al.: The coexistence of MET over-expression and an EGFR T790M mutation is related to acquired resistance to EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer. Oncotarget 2016;7:51311-51319.
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