Abstract 2167: Strengthening anti-cancer effects on non-small cell lung carcinoma by dual blockage of MET and EGFR in a context-dependent manner.

Non-small cell lung carcinoma (NSCLC) accounts for more than 80% of lung cancer, the leading cause of death among all cancer casualties. The MET receptor tyrosine kinase (RTK) is often co-expressed with EGFR in the NSCLC cells, and is an important alternative resistant mechanism for escaping EGFR-targeted therapy. To assess the benefit of dual blockage of MET and EGFR for NSCLC therapy, we investigated the activities of these two RTK pathways in several NSCLC cell lines carrying distinct cellular contexts, and determined their responses to SGX523 and erlotinib, the small molecule kinase inhibitors of MET and EGFR, respectively. Here, we showed that MET can cross-activate EGFR in MET-amplified or overexpressing cells via hetero-receptor dimerization, and the MET-dependent phosphorylation of EGFR can be abolished by SGX523 but not by erlotinib. More importantly, combined inhibition of MET and EGFR in vitro results in a maximal suppression of downstream ERK and AKT activation and of cell proliferation when their ligands (HGF and EGF) are present. Furthermore, we demonstrated that SGX523 and erlotinib combination strengthens anti-cancer activity in vivo in a cellular context-dependent manner. The combination led to regression of MET-amplified H1993 tumors by enhancing suppression of proliferation and inducing apoptosis, whereas significantly reduced MET-non-amplified H1373 tumor growths by suppression of proliferation without inducing apoptosis. Although SGX523 alone was sufficient to achieve near complete regression of MET-addicted EBC-1 tumors, its combination with erlotinib strongly inhibited viability of a population of SGX523-insensitive cells emerging from SGX523-treated EBC-1 tumor relapse. Our data suggest that dual blockage of MET and EGFR can enhance anti-cancer effects on NSCLC in a context-dependent manner, and provide a strong rationale and mechanisms for combining MET and EGFR inhibitors for NSCLC therapy. Citation Format: Yu-Wen Zhang, Ben Staal, Curt Essenburg, Steven Lewis, Dafna Kaufman, George F. Vande Woude. Strengthening anti-cancer effects on non-small cell lung carcinoma by dual blockage of MET and EGFR in a context-dependent manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2167. doi:10.1158/1538-7445.AM2013-2167