Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.
Cancer Cell, 2010/1/19;17(1):77-88.
Turke AB[1], 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, Jänne PA
Affiliations
PMID: 20129249DOI: 10.1016/j.ccr.2009.11.022
Impact factor: 38.585
Abstract
MET 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.
MeSH terms
Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Gene Amplification; Gene Expression; Hepatocyte Growth Factor; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Mice; Mutation; Polymerase Chain Reaction; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Quinazolinones; Receptors, Growth Factor; Signal Transduction; Xenograft Model Antitumor Assays
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