对De Novo Pyrimidine合成的代谢依赖是抗性卵巢癌中可针对性的脆弱性
Horacio Cardenas1, Yinu Wang1, Guangyuan Zhao1
1Northwestern University, Chicago, IL, United States.
Cancer research
|October 15, 2025
概括
由于代谢变化,卵巢癌会对化疗产生耐药性. 用布雷奎纳准新型金胺合成,使得瘤对药物产生抗药性.
科学领域:
- 在瘤学瘤学.
- 代谢途径 代谢途径
- 药物耐药性 药物耐药性 药物耐药性
背景情况:
- 卵巢癌 (OC) 是一种致命的恶性瘤,具有很高的基化疗耐药性.
- 代谢适应越来越被认为是癌症治疗耐药性的关键驱动因素.
研究的目的:
- 在卵巢癌中确定调节反应的关键代谢途径.
- 探索克服化疗耐药性的潜在治疗点.
主要方法:
- 对对思普拉丁敏感和耐药卵巢癌细胞的转录和代谢分析.
- 15N-谷氨胺流量分析,以评估新的皮里米丁合成.
- 在体外和体内使用DHODH抑制剂布雷奎纳 (BRQ) 结合卡博普拉丁的体外和体内研究.
主要成果:
- 抗西斯普拉丁的卵巢癌细胞表现出高调的de novo胺合成.
- 用布雷基纳向二基酸脱酶 (DHODH) 降低了细胞活力,改变了耐药细胞中的线粒体功能.
- 布雷奎纳减弱了瘤生长,并增强了对西斯普拉丁耐药卵巢癌的临床前模型中的卡博普拉丁疗效.
结论:
- 代谢重编程,特别是对de novo胺合成的获得依赖,有助于卵巢癌中的抗性.
- 针对 de novo pyrimidine 合成是一种有前途的策略,可以使卵巢瘤对化疗重新敏感.
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