Graham Laura, Schweizer Michael T
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.
Med Oncol. 2016 May;33(5):44. doi: 10.1007/s12032-016-0759-3. Epub 2016 Apr 4.
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.
去势抵抗性前列腺癌（CRPC）是晚期前列腺癌的必然致命表型，代表一种尽管睾酮水平降至去势水平（即≤50 ng/dL）但疾病仍进展所定义的临床状态。尽管对雄激素剥夺疗法（即促性腺激素释放激素激动剂/拮抗剂）耐药，但CRPC仍继续依赖雄激素受体（AR）信号通路。支持AR信号在去势抵抗状态中的重要性的是，新一代AR信号抑制剂恩杂鲁胺和阿比特龙已被证明能使转移性CRPC男性患者获得生存益处。然而，对这些药物的原发性和继发性耐药机制不可避免地导致疾病持续进展，这通常是AR信号重新激活的结果。随着对尽管有阿比特龙和恩杂鲁胺等药物但AR信号仍持续存在的潜在机制的认识不断增加，旨在更有效靶向AR信号的新一轮疗法正在出现。本综述将聚焦于CRPC耐药性更具临床相关性的机制以及我们目前针对这些机制开发药物的努力。
