MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling by Engelman Jeffrey A, Zejnullahu Kreshnik, Mitsudomi Tetsuya, Song Youngchul, Hyland Courtney, Park Joon Oh, Lindeman Neal, Gale Christopher-Michael, Zhao Xiaojun, Christensen James, Kosaka Takayuki, Holmes Alison J, Rogers Andrew M, Cappuzzo Federico, Mok Tony, Lee Charles, Johnson Bruce E, Cantley Lewis C, Jänne Pasi A in Science (New York, N.Y.) (2007). PubMed

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.

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