The androgen receptor is a critical target for the treatment of locally advanced and metastatic prostate cancer (PCa). Blocking AR signaling via castration or antiandrogens such as bicalutamide and enzalutamide results in tumor regression. However, resistance to AR-targeted therapy inevitably develops, marked by the outgrowth of castration-resistant prostate cancer (CRPC) cells. Mechanisms of CRPC include amplification of the AR gene, leading to overexpression of AR mRNA and protein, as well as expression of truncated AR splice variants. AR overexpression can convert bicalutamide to a weak agonist, thereby driving AR reactivation and ongoing cellular proliferation and survival. AR splice variants lack the COOH-terminal AR ligand binding domain (LBD) and function as constitutively-active, ligand-independent transcription factors. Recently, the chlorinated bisphenol A diglycidyl ether, EPI-001, was shown to bind to the AR NH2-terminal domain and inhibit AR signaling by interfering with coactivator recruitment. Here, we show that EPI-001 has a novel activity of mediating degradation of AR protein in various PCa cell lines, including cells driven by AR gene amplification and cells driven by AR splice variants. Cells displaying resistance to the next-generation antiandrogen enzalutamide were growth inhibited at EPI-001 concentrations corresponding to maximal AR degradation. Moreover, using VCaP cells as a model of AR overexpression, we show that EPI-001-mediated AR degradation prevents inappropriate agonist response to bicalutamide. This work provides proof-of-principle that targeting full-length and splice variant forms of the AR for degradation with EPI-001 may enhance the efficacy of conventional and next-generation antiandrogens for treatment of CRPC.

Citation Format: Lucas J. Brand, Scott M. Dehm. Chlorinated bisphenol A diglycidyl ether (EPI-001) mediates degradation of the androgen receptor in prostate cancer cells. [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 1325. doi:10.1158/1538-7445.AM2013-1325