Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, with disease progression frequently occurring despite the use of potent androgen receptor (AR)-targeted therapies. As AR signalling continues to drive tumour growth in this setting, new therapeutic strategies are being developed to disrupt the AR axis through both direct and indirect mechanisms. This review highlights a selection of promising agents in preclinical or clinical development that represent the next generation of therapies targeting AR signalling. Direct approaches include novel agents that degrade the AR or target domains beyond the conventional ligand-binding domain, aiming to overcome resistance to existing anti-androgens. Indirect strategies are designed to interfere with AR function by modulating AR-associated transcriptional co-regulators, chromatin accessibility, and other regulatory proteins, such as splicing factors, that are critical for sustaining AR-driven gene expression in prostate cancer. Together, these therapies form the basis of emerging strategies to more effectively suppress AR activity in CRPC. This review discusses AR-activating mechanisms, the mechanisms of action of these agents, their clinical development status, and their potential to reshape future treatment paradigms in CRPC.
去势抵抗性前列腺癌（CRPC）仍是临床治疗中的重大挑战，尽管已使用强效雄激素受体（AR）靶向疗法，疾病进展仍频繁发生。由于AR信号通路在此背景下持续驱动肿瘤生长，目前正在开发通过直接和间接机制破坏AR轴的新治疗策略。本综述重点介绍了一批处于临床前或临床开发阶段、代表下一代AR信号靶向疗法的潜力药物。直接策略包括可降解AR或靶向传统配体结合域以外功能域的新型药物，旨在克服现有抗雄激素药物的耐药性。间接策略则通过调控AR相关转录共调节因子、染色质可及性及其他调控蛋白（如对维持前列腺癌中AR驱动基因表达至关重要的剪接因子）来干扰AR功能。这些疗法共同构成了新兴策略的基础，旨在更有效地抑制CRPC中的AR活性。本文系统探讨了AR激活机制、相关药物的作用机理、临床研发进展及其重塑CRPC未来治疗格局的潜力。
肿瘤(癌症)患者之家