Double-strand DNA break (DSB)-inducing agents such as platinum analogues and poly (ADP-ribose) polymerase inhibitors (PARPis) exhibit significant antitumor activity in epithelial ovarian cancer (EOC). Approximately 50% of patients with EOC harbor genetic or epigenetic alterations of the homologous recombination (HR) DNA repair pathway and are highly responsive to these agents. However, resistance to DSB-inducing agents develops in the majority of patients and represents a major limitation for successful treatment of EOC. We recently defined a gene expression profile of “BRCAness” that correlates with responsiveness to double-strand DNA break-inducing agents (platinum and PARPis) in EOC. We applied this profile to the Connectivity Map to identify candidate compounds that might be able to enhance sensitivity to these agents. This analysis showed that the top-performing compound was the heat shock protein 90 (HSP90) inhibitor 17-allylamino-geldanamycin (17-AAG) with very high connectivity scores (>0.8) across several cell lines and concentrations (permutation p value < 0.00001). We then evaluated the ability of 17-AAG to enhance sensitivity to double-strand DNA break-inducing agents in a panel of ovarian cancer cell lines. Exposure to increasing concentrations of 17-AAG (0.02-0.1uM) was associated with increased sensitivity of 36M2 and OVCAR5 cells to carboplatin in a dose response manner. Similarly, exposure to increasing concentrations of 17-AAG (0.02-0.1uM) was associated with increased sensitivity of 36M2 and OVCAR5 cells to PARPi olaparib in a dose response manner. Exposure of these cell lines to combination of 17-AAG with carboplatin induced increased phosphorylation of H2AX (gamma H2AX) - a surrogate of DNA double-strand breaks - compared to carboplatin alone, as assessed by Western blotting. In conclusion, the HSP90 inhibitor 17-AAG enhances sensitivity of ovarian cancer cell lines to carboplatin and olaparib. The mechanism of this previously unknown, off-target effect, seems to be due to increasing DNA double strand breaks.

Citation Format: Chiara Battelli, Alexander Morse, Hai Hu, Elena Levantini, Gerburg Wulf, Panagiotis A. Konstantinopoulos. HSP90 inhibitor 17-allylamino-geldanamycin enhances sensitivity to double-strand DNA break-inducing agents (platinum and PARP inhibitors) in epithelial ovarian cancer. [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 3339. doi:10.1158/1538-7445.AM2013-3339

©2013 American Association for Cancer Research
2013