Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Co-targeting of the androgen receptor and Hsp90 in prostate cancer (#75)

Lisa Butler 1 2
  1. School of Medicine and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA, Australia
  2. South Australian Health and Medical Research Institute, Adelaide, SA, Australia

Inhibition of androgen receptor (AR) signaling is the goal of systemic therapies for advanced prostate cancer; however current strategies do not completely suppress AR activity and lead to the emergence of castration-resistant prostate cancer. Combining agents that target different aspects of AR expression or function has the potential to provide more complete inhibition of AR signaling and therefore improve patient outcomes. Inhibitors of heat shock protein 90 (Hsp90) are particularly attractive for inclusion in a combinatorial strategy as the AR relies on Hsp90 for its stability and ligand-binding capacity. In this study, we markedly enhanced the efficacy of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 to induce death of AR-dependent prostate cancer cells by co-treating with the AR antagonist bicalutamide, using low doses of each agent that were ineffective when used alone. Gene expression profiling revealed significantly enhanced inhibition of androgen signaling in combination-treated cells, which was associated with increased cytoplasmic localization of the AR. Importantly, the heat shock response that is elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced in cells co-treated with 17-AAG and bicalutamide. This study demonstrates that use of an Hsp90 inhibitor and AR antagonist in a combinatorial approach affords the potential to more effectively target AR signaling in prostate cancer cells while reducing treatment resistance, which could significantly improve outcomes for men with advanced prostate cancer.