阴茎驱动的mTOR信号维持了CRPC中对税种的抗性,并揭示了组合治疗的可针对性脆弱性
Ipek Bulut1,2, Buse Cevatemre1,3, Neslihan Yuksel-Catal2
1Koc University Research Center for Translational Medicine, Istanbul, Turkey.
Cell communication and signaling : CCS
|December 19, 2025
概括
梅宁蛋白在前列腺癌中驱动对税化疗的抗性. 抑制Menin或mTOR可以恢复治疗敏感性,并改善晚期前列腺癌患者的治疗结果.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 雄激素剥夺疗法 (ADT) 是前列腺癌 (PC) 的标准,但抗性发展,导致割耐性前列腺癌 (CRPC).
- 像多塞塔克塞尔 (Dtx) 和卡巴西塔克塞尔 (Cbz) 这样的税素用于CRPC,但治疗耐药性仍然是一个重大的临床挑战.
研究的目的:
- 确定新型治疗点,以克服CRPC中分类体的耐药性.
- 调查Menin在调解化学抵抗中的作用,并探索针对Menin的治疗方法.
主要方法:
- 已建立的抗多塞素CRPC模型.
- 进行了表观遗传药物查,以确定敏感剂.
- 进行了Menin (MEN1) 的功能衰竭,并分析了它对细胞增殖和化学抵抗的影响.
- 使用了整合性转录组 (RNA-seq) 和表观组 (CUT&RUN-seq) 分析.
- 通过绑定测定和救援实验验验证了Menin在mTOR和E2F通道中的作用.
- 分析了MEN1和mTOR联合表达的TCGA数据集.
- 在体外和体内评估使用mTOR抑制剂 (Torin-1) 和多塞的联合治疗.
主要成果:
- MLL-Menin和MLL-WDR5抑制剂通过诱导G2/M停止和亡来恢复分类体的敏感性.
- 阴膜枯竭选择性地损害了耐药细胞的增殖,并阻止了耐药性.
- 门调节mTOR信号传递和E2F向通路,与mTOR和Cyclin D1促进体结合.
- 在晚期转移性PC中,MEN1和mTOR被共同表达.
- 门抑制和mTOR抑制的组合协同增强了治疗反应.
- MEN1 knockdown 在体内废除了瘤生长.
结论:
- 梅宁是通过调节mTOR信号传递来调节CRPC中分类物耐药性的关键媒介.
- 针对Menin,单独或与mTOR抑制剂一起,提供了一种有前途的策略,以克服晚期前列腺癌中对标素的抗性.
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