Antiapoptotic proteins are commonly overexpressed in gliomas, contributing to therapeutic resistance. We recently showed that clinically achievable concentrations of the Bcl-2/Bcl-xL inhibitor ABT-737 failed to induce apoptosis in glioma cells, with persistent expression of survivin and Mcl-1. To address the role of these mediators in glioma apoptosis resistance, we analyzed the effects of YM-155, a survivin suppressant, on survival on a panel of glioma cell lines. YM-155 inhibited growth, and downregulated survivin and Mcl-1 in a dose- and cell line-dependent manner. Whereas U373, LN18, LNZ428, T98G, LN229, and LNZ308 cells exhibited an IC50 of 10-75 nM, A172 cells were resistant (IC50 ∼ 250 nM). No correlation was found between sensitivity to YM-155 and baseline expression of survivin or cIAP-1/cIAP-2/XIAP. However, strong correlation was observed between EGFR activation levels and YM-155 response, which was confirmed using EGFR-transduced versus wild-type cells. Because we postulated that decreasing Mcl-1 expression may enhance glioma sensitivity to ABT-737, we examined whether cotreatment with YM-155 promoted ABT-737 efficacy. YM-155 synergistically enhanced ABT-737-induced cytotoxicity and caspase-dependent apoptosis. Down-regulation of Mcl-1 using shRNA also enhanced ABT-737-inducing killing, confirming an important role for Mcl-1 in mediating synergism between ABT-737 and YM-155. As with YM-155 alone, sensitivity to YM-155 and ABT-737

Citation Format: Esther P. Jane, Daniel Premkumar, Joseph DiDomenico, Bo Hu, Shi-Yuan Cheng, Ian Pollack. YM-155 sensitizes malignant human glioma cells to ABT-737 via survivin and Mcl-1 downregulation in an EGFR-dependent context. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4100. doi:10.1158/1538-7445.AM2013-4100

©2013 American Association for Cancer Research
2013