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

By J. Bean, C. Brennan, Jin-Yuan Shih, Gregory Riely, A. Viale, Lu Wang, D. Chitale, N. Motoi, J. Szőke, S. Broderick and 13 more. Proceedings of the National Academy of Sciences of the United States of America, 2007

1,698 citations recorded by the source corpus.

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 EGFRT790M 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 EGFRT790M mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.

Subfields: Pathology and Forensic Medicine, Pulmonary and Respiratory Medicine, Surgery

View Paper: https://www.semanticscholar.org/paper/13d07eac0872b2fdc4e5dbe41921cf45606dbdee

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Pathology and Forensic Medicine

1. Carlos L. Arteaga
2. B. Chan
3. B. Hughes
4. N. Hynes
5. J. Massagué
6. D. Nguyen
7. J. Engelman
8. R. Roskoski

In Pulmonary and Respiratory Medicine

1. William Pao
2. Jin-Yuan Shih
3. Shang-Gin Wu
4. Carlos L. Arteaga
5. J. Engelman
6. B. Hughes
7. B. Chan
8. P. Jänne

In Surgery

1. J. Engelman

Citations in the corpus

• ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics (2014, background): “…are used to determine the next course of therapy for an individual patient as the (acquired) alterations identified in a single biopsymay not reflect all of the resistant clones in multiple metastatic sites in an individual patient (Bean et al., 2007; Engelman et al., 2007; Turke et al., 2010).”
• HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. (2012, background): “This sample was also negative for amplification of the gene encoding the MET tyrosine kinase, which constitutes another mechanism of acquired resistance (20).”
• Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers (2012, background): “Studies from other oncogene addiction paradigms suggest that activation of alternative RTKs can lead to resistance to kinase inhibitors (19, 29, 30).”
• Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. (2015, background): “Unfortunately a wide variety of mechanisms are being discovered including; ALK amplification, EGFR/HER1, HER2 and HER3 up-regulation, cKIT amplification and various ALK mutations including L1196M (analogous to T790M for EGFR) (107-110).”
• An overview of the c-MET signaling pathway (2011, background): “Interestingly, recent research has shown that non-small cell lung carcinomas with acquired resistance to EGFR inhibitors tend to show amplifications in MET [Bean et al. 2007; Engelman et al. 2007].”
• Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer (2010, background): “In patients, the major mechanisms of primary and acquired resistance (see below) are the same for both drug”