Evodiamine induces apoptosis and enhances apoptotic effects of erlotinib in wild-type EGFR NSCLC cells via S6K1-mediated Mcl-1 inhibition.

Erlotinib is effective in NSCLC patients with known drug-sensitizing EGFR mutations, but its clinical efficacy in patients with wild-type EGFR or acquired resistance to erlotinib remains modest. Evodiamine is a chemical extracted from the Evodia rutaecarpa (Juss.) Benth, we showed that evodiamine could induce anti-proliferation and apoptosis in four wild-type EGFR NSCLC cell lines, and combining evodiamine with erlotinib might successfully inhibit cell proliferation and survival in wild-type EGFR NSCLC cells, characterized as erlotinib-resistant. In addition, evodiamine plus erlotinib significantly increased the apoptotic rate of NSCLC cells, as compared to single agent treatment alone. Further investigation of the mechanism underlying these effects revealed that evodiamine plus erlotinib might downregulate Mcl-1 expression through the mTOR/S6K1 control of its translation. Thus, our study has revealed evodiamine as a pertinent sensitizer to erlotinib and the strategy of combining erlotinib with evodiamine appears to be an attractive option for reversing resistance to erlotinib.