Novel anti-androgen receptor signaling agents: Understanding the mechanisms of resistance

Prostate cancer remains an intractable threat to the lives of men worldwide. Although deaths from prostate cancer (PCa) in the United States have declined in recent years, in other parts of the world Pca mortality is increasing. The introduction of 2nd generation anti-androgen receptor agents into the therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has resulted in modestly increased survival advantages as demonstrated by initial clinical trials. However, analysis of the molecular pathways affected by these agents may lead to new insight into mechanisms of resistance that drive mCRPC, including proliferation and survival signaling pathways that are derepressed by maximum repression of androgen signaling. Combination therapies that involve anti-AR signaling agents together with agents that target these pathways establish a paradigm for the development of more effective treatment of mCRPC. In this review, we briefly summarize the current clinical trial literature with regard to novel anti-AR signaling agents such as abiraterone acetate and enzalutamide. We discuss observational data that point to mechanisms of resistance that emerged from these studies. We further present and discuss recent experimental studies that address the mechanisms of resistance to these treatments. Finally, we discuss novel and rational therapeutic approaches, including combination therapy, for patients with mCRPC.