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DOI: 10.1073/pnas.0710370104
¤ OpenAccess: Green
This work has “Green” OA status. This means it may cost money to access on the publisher landing page, but there is a free copy in an OA repository.

<i>MET</i> amplification occurs with or without <i>T790M</i> mutations in <i>EGFR</i> mutant lung tumors with acquired resistance to gefitinib or erlotinib

James Bean,Cameron Brennan,Jin‐Yuan Shih,Gregory J. Riely,Agnès Viale,Lu Wang,Dhananjay Chitale,Noriko Motoi,János Szőke,Stephen Broderick,Marissa N. Balak,W.C. Chang,Chong Jen Yu,Adi F. Gazdar,Harvey I. Pass,Valerie W. Rusch,William L. Gerald,Shiu Feng Huang,Pan Chyr Yang,Vincent A. Miller,Marc Ladanyi,Chih Hsin Yang,William Pao

T790M
Gefitinib
Erlotinib
2007
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.
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    <i>MET</i> amplification occurs with or without <i>T790M</i> mutations in <i>EGFR</i> mutant lung tumors with acquired resistance to gefitinib or erlotinib” is a paper by James Bean Cameron Brennan Jin‐Yuan Shih Gregory J. Riely Agnès Viale Lu Wang Dhananjay Chitale Noriko Motoi János Szőke Stephen Broderick Marissa N. Balak W.C. Chang Chong Jen Yu Adi F. Gazdar Harvey I. Pass Valerie W. Rusch William L. Gerald Shiu Feng Huang Pan Chyr Yang Vincent A. Miller Marc Ladanyi Chih Hsin Yang William Pao published in 2007. It has an Open Access status of “green”. You can read and download a PDF Full Text of this paper here.