在CRC中对KRAS抑制的同时存在的遗传和非遗传抵抗机制
Salvador Alonso1,2, Kevan Chu1,3, Marie J Parsons1
1Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY.
bioRxiv : the preprint server for biology
|August 13, 2025
概括
克拉斯抑制剂对结肠直肠癌 (CRC) 是有前途的,但耐药性是一个挑战. 向TBK1可能会克服早期的炎症反应,并提高KRAS突变的CRC的治疗疗效.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- KRAS突变导致45-50%的结直肠癌 (CRC) 病例.
- 针对KRAS的疗法面临着先发性和获得性耐药性,限制了临床疗效.
- 了解耐药机制对于改善CRC治疗结果至关重要.
研究的目的:
- 研究结直肠癌中对联合KRASG12C和EGFR抑制的急性反应和抵抗机制.
- 识别能够克服药物耐药性的分子标.
主要方法:
- 针对患者活检 (治疗前,治疗期间,进展) 的向外体序列和单细胞空间转录组学.
- 对遗传事件和转录性适应性状态的分析.
- 利用人类和小鼠器官模型来研究药物诱导的程序.
主要成果:
- 获得的遗传事件通常是亚克隆的,并与转录的适应性状态共存在进展.
- 中细胞,YAP和胎儿样特征在耐药瘤中占主导地位.
- 早期治疗诱导了瘤细胞内在的炎症程序,先前的药物耐药性相关的胎儿类程序.
结论:
- 显著的内异质性和多样化的适应状态有助于耐药性.
- 药物诱导的炎症程序是癌细胞自主的,并且在抵抗之前.
- 抑制TBK1是一种潜在的策略,可以废除早期的炎症反应,并增强CRC中KRAS抑制的有效性.
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