DHODH作为一种可向的代谢阿基里斯脚跟,用于抗化疗B-ALL的B-ALL
Yuxuan Liu1, Haowen Jiang1, Jingjing Liu2
1Stanford University, Stanford, California, United States.
Blood
|January 23, 2026
概括
在B细胞急性淋巴细胞白血病 (B-ALL) 中,活性信号驱动葡萄糖依赖和胺合成. 抑制二基酸脱酶 (DHODH) 显示出治疗化疗耐药B-ALL的前景.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- B细胞急性淋巴细胞白血病 (B-ALL) 的复发是与化疗耐药性相关的重大挑战.
- 激活的B细胞信号通路和增加的葡萄糖代谢与更高的复发风险有关.
研究的目的:
- 调查B-ALL.活跃B细胞信号传递,葡萄糖代谢和治疗脆弱性之间的联系.
- 为了确定抗化疗性B-ALL的新型治疗点.
主要方法:
- 利用同位素追踪来评估活性信号 (高酸化核糖体蛋白S6) 的B-ALL细胞中的代谢途径.
- 研究了mTOR信号传递和CAD激活在胺合成中的作用.
- 在体外和体内使用患者衍生异体移植 (PDX) 评估了二基酸脱酶 (DHODH) 抑制剂 (BAY-2402234) 的疗效.
主要成果:
- 有活跃信号传导 (pS6+) 的B-ALL细胞对新核酸合成具有很高的葡萄糖依赖性.
- 活跃的mTOR信号通过激活CAD来调节金字胺合成.
- DHODH表达与复发和生存率差相关; DHODH抑制有效地杀死pS6+ B-ALL细胞,并在临床前模型中改善生存率.
结论:
- 在B-ALL中,主动信号产生了对pyrimidine合成的依赖,使其成为一个漏洞.
- 抑制DHODH代表了对抗化疗性B-ALL的有前途的治疗策略,特别是在具有活跃信号通路的患者中.
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