Preclinical Development Overcoming Erlotinib Resistance in EGFR Mutation–Positive Non–Small Cell Lung Cancer Cells by Targeting Survivin

Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation–positive non–small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR–TKIs contributes to EGFR–TKI-induced apoptosis in EGFRmutation– positive NSCLC cells. We have now investigated the role of survivin expression in EGFR–TKI resistance induced by PTEN loss. The EGFR–TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation–positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapywithYM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation–positive, PTEN-deficient NSCLC cells in nude mice to a greater extent thandid treatmentwith either drug alone. These results thus indicate that persistent activation of signaling by the AKT–survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation–positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR–TKI resistance in EGFR mutation–positive NSCLC. Mol Cancer Ther; 11(1); 204–13. 2011 AACR.