Comparison Of Surface-Directed And Classic Androgen Receptor Antagonists

Background: The androgen receptor (AR) surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells and these effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared activities of MJC13 and the classic AR antagonist flutamide. Method and Results: MJC13 and flutamide inhibit all dihydrotestosterone (DHT)-dependent genes in LNCaP PC cells and both compounds are equally effective. Control ChIP assays confirm that MJC13 inhibits AR binding to the prostate specific antigen (PSA) promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects of castrate resistant prostate cancer (CRPC) reveals that it inhibits a flutamide-dependent AR mutant (ART877A), but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR), which can co-opt androgen-dependent signaling networks in CRPC. While flutamide inhibits AR interactions with the coactivator SRC2, it does not affect β-catenin binding. In contrast, MJC13 inhibits AR interactions with both coregulators and, unlike flutamide, strongly inhibits amplification of AR activity obtained with SRC2 and β-catenin. MJC13 also preferentially inhibits β-catenin-enhanced cell division in LNCaP cells relative to flutamide. Conclusion: Our findings suggest that a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in some forms of CRPC. Citation Format: Ji Ho Suh, Arundhati Chattopadhyay, Douglas H. Sieglaff, Cheryl L. Storer, Marc B. Cox, Paul Webb. Comparison of surface-directed and classic androgen receptor antagonists. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 83. doi:10.1158/1538-7445.AM2015-83