Heat shock protein 90 (HSP90) is an important cancer therapeutic target. HSP90 chaperone activity maintains the conformation, stability and function of mutated variants and over-expressed oncogenic client proteins responsible for driving the proliferation of human cancer. To further increase the efficacy and specificity of HSP90 inhibitor treatment, cancer cell response to HSP90 inhibition can be modulated through the use of combinatorial therapeutics. An siRNA screen targeting 7,593 genes encoding proteins considered to be druggable was used to identify candidates that modulate the cellular response to HSP90 inhibition by 17-AAG. This approach may provide information on the potential mechanisms of cancer cell resistance, allow selection of responsive patient populations based on the identification of novel biomarkers, and potentially provide targets for combinatorial therapy. Screening produced robust data with an average plate z-factor of 0.6 and results were validated with an alternative chemotype of HSP90 inhibitor. As anticipated, significant sensitisation to HSP90 inhibition was observed with HSF1 depletion, and conversely resistance was observed with NQO1 depletion. Sensitisation candidates were the main focus of analysis as they potentially represent the more amenable drug targets. There was an enrichment of mitochondrial constituents, cell cycle regulators and post-translational protein modifiers that when depleted produced significant sensitisation to HSP90 inhibitors in human carcinoma cells. Future work aims to reveal the molecular mechanisms underpinning the sensitisation phenotypes observed and to identify points of intervention for clinical combinatorial therapy with HSP90 inhibitors.

Citation Format: Jennifer Howes, Bing-Feng Lu, Marissa Powers, Paul Clarke, Paul Workman. Synthetic lethal screen identifies candidates that modulate cancer cell sensitivity in response to HSP90 inhibition. [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 1133. doi:10.1158/1538-7445.AM2013-1133

©2013 American Association for Cancer Research
2013