Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC
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AbstractMET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations; of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy.
All Author(s) ListTurke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L, Lindeman NI, Murphy C, Akhavanfard S, Yeap BY, Xiao Y, Capelletti M, Iafrate AJ, Lee C, Christensen JG, Engelman JA, Janne PA
Journal nameCancer Cell
Year2010
Month1
Day19
Volume Number17
Issue Number1
PublisherElsevier (Cell Press)
Pages77 - 88
ISSN1535-6108
eISSN1878-3686
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesCell Biology; CELL BIOLOGY; Oncology; ONCOLOGY

Last updated on 2020-30-11 at 23:31