Simultaneous inhibition of c-Met and EGFR for overcoming resistance to EGFR-therapy in NSCLC

Abstract

Mesenchymal-epithelial transition factor (MET),the only high affinity

receptor for hepatocyte growth factor (HGF), plays an important role in human carcinoma and is recognized as a therapeutic target. In addition, c- Met and EGFR are receptor tyrosine kinases that may cross-talk in driving the development and progression of non–small cell lung cancer (NSCLC). In this study, it described the small molecular compound ABN401, a novel inhibitor of MET kinase, and the combination therapy with EGFR tyrosine kinase inhibitors, including Erlotinib, Afatinib and Tagrisso. The results from this study show that this inhibitor potently blocks MET phosphorylation and activation of its key downstream effectors especially in MET amplified lung cancer cell lines. MET amplified mouse tumor models also show dose-dependent inhibition of tumor growth. In a further exploration of potential treatment for MET activation and signaling through intracellular signaling cascade enhanced by EGFR, the results showed that combination treatment with EGFR inhibitors positively repress tumor growth compared to single treatment both in vitro and in vivo. This study suggests that ABN401 is a potent and selective MET inhibitor that may have therapeutic potential in lung cancer treatment. Moreover, development of combination therapies by utilizing MET and EGFR inhibitors may greatly improve treatment effect in lung cancer patients.