Therapeutic Discovery Combined TherapywithMutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer

Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib bydifferentmechanisms: PC-9/HGF cellswith an exon 19 deletion,H1975 with anL858Rmutation, andHCC827ERwith an exon 19deletion,with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790Mmutation, andMet amplification, respectively. WZ4002 inhibited the growth ofH1975 cells with a gatekeeper T790Mmutation, but did not inhibit the growth ofHCC827ER and PC-9/HGF cells. HGF triggered the resistance ofH1975 cells toWZ4002,whereas E7050 sensitizedHCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severecombined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associatedwith the inhibition of EGFR andMet phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790Mmutation,Met amplification, andHGF overexpression. Further evaluations in clinical trials are warranted. Mol Cancer Ther; 11(10); 1–9. 2012 AACR.