O1-076 - Met Kinase Inhibitor E7050 Reverses Three Different Mechanisms of Hepatocyte Growth Factor-Induced Tyrosine Kinase Inhibitor Resistance in EGFR Mutant Lung Cancer

Abstract

ABSTRACT Purpose Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant lung cancer cells by activating Met and the downstream PI3K/Akt pathway. Moreover, continuous exposure of HGF accelerates emergence of EGFR-TKI-resistant clones. The present study was carried out to determine whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. Experimental design The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992) and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR-mutant human lung cancer cell lines PC-9 and HCC827 with exon 19 deletion, and H1975 with T790M secondary mutation. As an in vivo model, PC-9 cells mixed with HGF-producing fibroblasts, MRC-5, were subcutaneously inoculated into SCID mice and the therapeutic effects of E7050 combined with gefitinib were examined. Results Our results indicated that E7050 circumvented resistance to all of the reversible, irreversible and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 combined with gefitinib-induced marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. Conclusions A new Met kinase inhibitor, E7050, reverses three different mechanisms of gefitinib resistance induced by HGF, suggesting the usefulness of E7050 for overcoming HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.