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.
Medical oncology (Northwood, London, England). 2016 Apr 04 [Epub]
Laura Graham, Michael T Schweizer
Department of Medicine, University of Washington, Seattle, WA, 98104, USA., Division of Oncology, Department of Medicine, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.