Targeting persistent androgen receptor signaling in castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC), the invariably lethal phenotype of advanced prostate cancer, represents a clinical state defined by disease progression despite reduction of testosterone to castrate levels (i.e., ≤50 ng/dL). Although resistant to androgen-deprivation therapy (i.e., LHRH agonists/antagonists), CRPC continues to depend on the androgen receptor (AR)-signaling pathway. Supporting the importance of AR-signaling in a castration-resistant state, the next-generation AR-signaling inhibitors enzalutamide and abiraterone have been shown to afford a survival benefit in men with metastatic CRPC. However, primary and secondary resistance mechanisms to these agents inevitably drive continued disease progression—often as a result of re-activation of AR-signaling. With increased understanding of the mechanisms underlying how continued AR-signaling occurs in spite of drugs like abiraterone and enzalutamide, a new wave of therapies is emerging designed to more effectively target AR-signaling. This review will focus on the more clinically relevant mechanisms of CRPC drug resistance and our ongoing efforts to develop drugs to target these mechanisms.