Abstract 1231: Differential roles of trans-phophorylated EGFR, HER2, HER3 and RET as heterodimerization partenrs of MET in lung cancer with MET amplification

Background: MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumor types. We investigated the roles and mechanisms of RTK heterodimerization in lung cancer with MET amplification. Methods: With the use of an RTK array, we identified several phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays. Results: We identified EGFR, HER2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor, but not by treatment with their spcific inhibitors. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signaling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signaling. Conclusion: Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET play differential roles in tumor development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerization partners of MET in lung cancer with MET amplification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1231. doi:1538-7445.AM2012-1231