去势耐受性前列腺癌症中的雄激素受体再激活：机制、表观遗传学适应和治疗脆弱性
Androgen receptor reactivation in castration-resistant prostate cancer: mechanisms, epigenetic adaptation, and therapeutic vulnerabilities.
摘要(中文译文)
去势抵抗性前列腺癌（CRPC）仍然是一个棘手的临床难题，尽管雄激素剥夺治疗和下一代雄激素受体（AR）通路抑制剂已大幅改善患者治疗。CRPC并非单纯的雄激素非依赖性疾病。在许多情况下，肿瘤细胞在去势条件下仍依赖持续存在或恢复的AR信号传导。AR再激活由多种相互重叠的机制驱动，包括AR扩增、AR过表达、配体结合域突变、AR剪接变异体、瘤内雄激素合成、旁路信号传导以及AR共调节因子改变。AR轴还与DNA损伤修复相关联。例如，PARP-1既可支持DNA修复，也可支持AR驱动的转录，这为在特定患者中联合AR靶向治疗与PARP抑制提供了依据。表观遗传适应是这一过程中的另一关键层面。染色质可及性改变、AR cistrome重分布、先锋因子、增强子活性以及染色质修饰共因子可重塑AR依赖性转录。这些变化帮助肿瘤细胞维持AR信号传导，同时也促进异质性、谱系可塑性及更具侵袭性的表型。近期单细胞转录组学和表观基因组学研究进一步显示，CRPC包含多种耐药细胞状态，这些状态可能在治疗过程中发生变化。重要的是，这些耐药机制也可能创造治疗机会。当前及新兴策略包括AR降解剂、AR N端结构域抑制剂、类固醇生成及旁路通路抑制剂、PARP抑制剂，以及靶向EZH2、BET蛋白、p300/CBP、LSD1或HDAC的表观遗传治疗。生物标志物指导的治疗，包括AR变异体、DNA修复缺陷、ctDNA谱及染色质状态，可能有助于为CRPC患者选择更优的治疗方案。
Abstract
Castration-resistant prostate cancer (CRPC) remains a difficult clinical problem, although androgen deprivation therapy and next-generation androgen receptor (AR) pathway inhibitors have greatly improved patient treatment. CRPC is not simply an androgen-independent disease. In many cases, tumor cells still depend on persistent or restored AR signaling under castrate conditions. AR reactivation is driven by several overlapping mechanisms, including AR amplification, AR overexpression, ligand-binding domain mutations, AR splice variants, intratumoral androgen synthesis, bypass signaling, and altered AR co-regulators. The AR axis is also connected with DNA damage repair. For example, PARP-1 can support both DNA repair and AR-driven transcription, which provides a rationale for combining AR-targeted therapy with PARP inhibition in selected patients. Epigenetic adaptation is another key layer in this process. Changes in chromatin accessibility, AR cistrome redistribution, pioneer factors, enhancer activity, and chromatin-modifying cofactors can reshape AR-dependent transcription. These changes help tumor cells maintain AR signaling and also promote heterogeneity, lineage plasticity, and more aggressive phenotypes. Recent single-cell transcriptomic and epigenomic studies further show that CRPC contains diverse resistant cell states, which may change during treatment. Importantly, these resistance mechanisms may also create therapeutic opportunities. Current and emerging strategies include AR degraders, AR N-terminal domain inhibitors, inhibitors of steroidogenesis and bypass pathways, PARP inhibitors, and epigenetic therapies targeting EZH2, BET proteins, p300/CBP, LSD1, or HDACs. Biomarker-guided treatment, including AR variants, DNA repair defects, ctDNA profiles, and chromatin states, may help select better therapies for CRPC patients.
如何引用
AMA
Juntao Guo, Ke Wu, Zheng Ma, Shuai Guo, Fei Wang, Lingxiang Lu. Androgen receptor reactivation in castration-resistant prostate cancer: mechanisms, epigenetic adaptation, and therapeutic vulnerabilities.. Frontiers in oncology. 2026; doi:10.3389/fonc.2026.1837998.
APA
Juntao Guo, Ke Wu, Zheng Ma, Shuai Guo, Fei Wang, Lingxiang Lu (2026). Androgen receptor reactivation in castration-resistant prostate cancer: mechanisms, epigenetic adaptation, and therapeutic vulnerabilities.. Frontiers in oncology. https://doi.org/10.3389/fonc.2026.1837998
GB/T 7714
Juntao Guo, Ke Wu, Zheng Ma, Shuai Guo, Fei Wang, Lingxiang Lu. Androgen receptor reactivation in castration-resistant prostate cancer: mechanisms, epigenetic adaptation, and therapeutic vulnerabilities.[J]. Frontiers in oncology, 2026 doi:10.3389/fonc.2026.1837998.
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