Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Curr Opin Oncol. 2019 May;31(3):175-182. doi: 10.1097/CCO.0000000000000520.
Prostate cancer (PCa) is diagnosed in one out of every nine men and is the second leading cause of cancer death among men. Although therapies targeting the androgen receptor (AR) are highly effective, development of resistance is universal and remains a major therapeutic challenge. Nonetheless, signaling via AR is frequently maintained despite standard androgen-signaling inhibition. We review the current understanding of mechanisms of resistance as well as therapeutic approaches to improving treatment of PCa via targeting of the AR.
Resistance to AR-targeting therapies may be mediated by several mechanisms, including amplification, mutation, and alternative splicing of AR; intratumoral androgen synthesis; activation of alternative signaling pathways; and in a minority of cases, emergence of AR-independent phenotypes. Recent trials demonstrate that intensification of androgen blockade in metastatic castration-sensitive PCa can significantly improve survival. Similar strategies are being explored in earlier disease states. In addition, several other cellular signaling pathways have been identified as mechanisms of resistance, offering opportunities for cotargeted therapy. Finally, immune-based approaches are in development to complement AR-targeted therapies.
Targeting the AR remains a critical focus in the treatment of PCa.
前列腺癌（PCa）在每九个男性中就有一人被诊断出患有该病，是男性癌症死亡的第二大主要原因。尽管针对雄激素受体（AR）的治疗方法非常有效，但耐药性的发展是普遍存在的，仍然是一个主要的治疗挑战。尽管如此，尽管标准的雄激素信号抑制，AR 的信号传导仍经常被维持。我们回顾了耐药机制的现有认识，以及通过靶向 AR 改善 PCa 治疗的治疗方法。
AR 靶向治疗的耐药性可能通过多种机制介导，包括 AR 的扩增、突变和选择性剪接；肿瘤内雄激素合成；替代信号通路的激活；在少数情况下，出现 AR 非依赖性表型。最近的试验表明，在转移性去势敏感型 PCa 中强化雄激素阻断可以显著提高生存率。在早期疾病状态下也正在探索类似的策略。此外，已经确定了几种其他细胞信号通路作为耐药机制，为联合靶向治疗提供了机会。最后，正在开发基于免疫的方法来补充 AR 靶向治疗。
靶向 AR 仍然是 PCa 治疗的关键重点。
