1. MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
- Author
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Youngchul Song, Courtney Hyland, Christopher-Michael Gale, Joon Oh Park, Pasi A. Jänne, Tony Mok, Kreshnik Zejnullahu, Tetsuya Mitsudomi, Jeffrey A. Engelman, Xiaojun Zhao, Federico Cappuzzo, Alison J. Holmes, James J. Christensen, Lewis C. Cantley, Neal I. Lindeman, Takayuki Kosaka, Bruce E. Johnson, Andrew M. Rogers, and Charles Lee
- Subjects
Indoles ,Lung Neoplasms ,Receptor, ErbB-3 ,Antineoplastic Agents ,CHO Cells ,Biology ,Proto-Oncogene Mas ,Phosphatidylinositol 3-Kinases ,T790M ,Cricetulus ,Gefitinib ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Cricetinae ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Receptors, Growth Factor ,heterocyclic compounds ,ERBB3 ,Sulfones ,Epidermal growth factor receptor ,Enzyme Inhibitors ,Phosphorylation ,skin and connective tissue diseases ,Lung cancer ,Erlotinib Hydrochloride ,neoplasms ,Cell Proliferation ,Multidisciplinary ,Gene Amplification ,Proto-Oncogene Proteins c-met ,medicine.disease ,respiratory tract diseases ,Drug Resistance, Neoplasm ,Quinazolines ,Cancer research ,biology.protein ,Erlotinib ,EGFR Activating Mutation ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,medicine.drug - Abstract
The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.
- Published
- 2007
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