title: MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.
abstract: In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFR(T790M) mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFR(T790M) mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.
authors: Human Oncology and Pathogenesis Program, Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors: James
authors: J
authors: Bean
authors: Cameron
authors: C
authors: Brennan
authors: Jin-Yuan
authors: JY
authors: Shih
authors: Gregory
authors: G
authors: Riely
authors: Agnes
authors: A
authors: Viale
authors: Lu
authors: L
authors: Wang
authors: Dhananjay
authors: D
authors: Chitale
authors: Noriko
authors: N
authors: Motoi
authors: Janos
authors: J
authors: Szoke
authors: Stephen
authors: S
authors: Broderick
authors: Marissa
authors: M
authors: Balak
authors: Wen-Cheng
authors: WC
authors: Chang
authors: Chong-Jen
authors: CJ
authors: Yu
authors: Adi
authors: A
authors: Gazdar
authors: Harvey
authors: H
authors: Pass
authors: Valerie
authors: V
authors: Rusch
authors: William
authors: W
authors: Gerald
authors: Shiu-Feng
authors: SF
authors: Huang
authors: Pan-Chyr
authors: PC
authors: Yang
authors: Vincent
authors: V
authors: Miller
authors: Marc
authors: M
authors: Ladanyi
authors: Chih-Hsin
authors: CH
authors: Yang
authors: William
authors: W
authors: Pao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D002897:Chromosomes, Human, Pair 7; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib