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Abstract
Abstract Receptor tyrosine kinases are canonically activated by dimerization induced by the binding of a cognate ligand. This leads to autophosphorylation of the receptor molecules by their intrinsic kinase domains and the recruitment of intracellular protein complexes to initiate signaling. In many human cancers, receptor tyrosine kinases are aberrantly activated to promote proliferative signaling, thus driving tumor growth. The MET proto-oncogene is amplified in approximately 5% of non-small-cell lung cancers (NSCLC), a disease in which aberrant signaling through the epidermal growth factor receptor (EGFR) or the anaplastic lymphoma kinase is known to be oncogenic. The Met receptor tyrosine kinase is overexpressed and constitutively active in cell lines derived from MET-amplified tumors, and Met activity is required for proliferation. Furthermore, Met activity is sufficient to promote the phosphorylation of EGFR and its homologs ErbB2 and ErbB3 in the presence of inhibitors targeting EGFR, ErbB2, and Src family kinases. We show that Met utilizes the EGFR, ErbB2 and ErbB3 proteins as scaffolds to broaden downstream oncogenic signaling and promote cancer cell proliferation. The contribution of EGFR and its homologs to Met signaling in NSCLC will be presented with a focus on ErbB family kinases required for proliferation in MET-amplified NSCLC. Understanding the mechanisms by which Met drives proliferative signaling in NSCLC will become crucial as Met-targeted therapies become available in the clinic. Citation Format: Yaakov E. Stern, Andrea Z. Lai, Morag Park. The Met receptor tyrosine kinase drives signaling through EGFR and ErbB3 in Met-amplified non-small-cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-77. doi:10.1158/1538-7445.AM2014-LB-77
Published Version
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