一种双阴性前列腺癌亚型易受SWI/SNF向降解分子的破坏
Phillip Thienger1, Irene Paassen1, Xiaosai Yao2,3
1Department for Biomedical Research, University of Bern, Bern, 3008, Switzerland.
bioRxiv : the preprint server for biology
|September 15, 2025
概括
降解SWI/SNFATPases的蛋白质溶解向嵌合体 (PROTAC) 疗法在治疗抵抗割的前列腺癌 (CRPC) 方面表现有前途. 这些药物对AR依赖和WNT信号CRPC都有效,提供了新的治疗途径.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 蛋白质溶解向嵌合体 (PROTAC) 疗法提供了一种新的策略,以向AR-依赖性割抵抗性前列腺癌 (CRPC-AR) 中的雄激素受体 (AR) 信号.
- 在AR阴性CRPC中,特别是WNT信号依赖子型 (CRPC-WNT) 中,SWI/SNF ATPase向剂的有效性仍然在很大程度上未被探索.
- 在全球范围内,CRPC-WNT占CRPC死亡的很大一部分.
研究的目的:
- 研究SWI/SNF向剂在AR阴性CRPC,特别是CRPC-WNT亚组中的治疗潜力.
- 阐明SWI/SNF向影响CRPC-WNT细胞活力的分子机制.
- 在CRPC-WNT信号通路中识别潜在的治疗点.
主要方法:
- 使用的细胞系和来自CRPC的有机体模型.
- 管理SWI/SNF向的PROTACs,以评估它们对细胞活性的影响.
- 研究了SWI/SNF ATPase SMARCA4,TCF7L2和CRPC-WNT中的MAPK信号通路之间的相互作用.
主要成果:
- 针对SWI/SNF的PROTAC治疗降低了CRPC-AR和CRPC-WNT模型的可行性.
- 在CRPC-WNT模型中发现SMARCA4枯竭会干扰转录调节器TCF7L2.2.
- 确定TCF7L2是CRPC-WNT扩散的关键驱动因素,通过MAPK信号轴运作.
结论:
- 针对SWI/SNF的疗法对AR-依赖和AR-负WNT信号CRPC都显示出有效性.
- 通过影响MAPK通路,SMARCA4的枯竭破坏了CRPC-WNT中TCF7L2介导的增殖.
- 针对TCF7L2的DNA结合或MAPK信号传递是CRPC-WNT的一种有前途的治疗策略.
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