MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.
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.
Bean
James
J
Human Oncology and Pathogenesis Program, Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Brennan
Cameron
C
Shih
Jin-Yuan
JY
Riely
Gregory
G
Viale
Agnes
A
Wang
Lu
L
Chitale
Dhananjay
D
Motoi
Noriko
N
Szoke
Janos
J
Broderick
Stephen
S
Balak
Marissa
M
Chang
Wen-Cheng
WC
Yu
Chong-Jen
CJ
Gazdar
Adi
A
Pass
Harvey
H
Rusch
Valerie
V
Gerald
William
W
Huang
Shiu-Feng
SF
Yang
Pan-Chyr
PC
Miller
Vincent
V
Ladanyi
Marc
M
Yang
Chih-Hsin
CH
Pao
William
W
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*
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