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Updated: Jun 13, 2025

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在KRAS突变癌症中解开CDK9/PP2A/ERK网络在转录暂停释放和补充激活中

Yafang Wang¹, Lansong Xu^1,2, Lijun Ling¹

¹Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, P. R. China.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|September 10, 2024

概括

选择性CDK9抑制对KRAS突变癌症有希望,但面临抵抗. 将CDK9抑制剂与KRAS/MAPK通路或TME调节结合起来,可以克服耐药性并提高疗效.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
癌症治疗癌症治疗

背景情况:

选择性抑制P-TEFb复合体,特别是CDK9,是一种有前途的癌症治疗策略.
目前的CDK9抑制剂主要有效于血液性恶性瘤,在KRAS突变癌症等固体瘤中有效性有限.

研究的目的:

研究CDK9抑制剂在KRAS突变癌症中的疗效.
阐明对CDK9抑制剂耐药性的机制.
确定结合策略以克服耐药性并增强治疗结果.

主要方法:

在实验室和体内 (裸体小鼠异种移植) 研究KRAS突变癌症模型中的CDK9抑制剂.
分析信号通路,包括ERK-MYC,原瘤基因,直接早期基因和补充级联.
研究了CDK9/Src相互作用在调节PP2Ac活性和RNA聚合酶II酸化中的作用.
包括CDK9抑制剂与KRAS/MAPK通路抑制剂和免疫调节剂的评估组合疗法.

主要成果:

抑制CDK9显示出初始的体外反应,但在体内不令人满意的疗效.
抵抗机制包括补偿ERK-MYC激活,原基因恢复,IEG上调和瘤免疫抑制.
矛盾的是,CDK9/Src相互作用调节PP2Ac活性,促进ERK酸化和RNA聚合酶II释放.
与KRAS/MAPK通路抑制剂共同向CDK9,消除了ERK-MYC激活,克服了耐药性.
通过补充系统干预调节瘤微环境,增强了CDK9抑制剂反应.

结论:

仅仅抑制CDK9对KRAS突变癌症是不够的,因为有抵抗机制.
针对CDK9和KRAS/MAPK通路的组合策略在控制KRAS突变癌症方面有效.
补充系统干预可以通过调节瘤微环境来提高CDK9抑制剂的有效性.
临床前数据支持临床试验,将CDK9抑制剂与KRASi/SOS1i/MEKi或KRAS突变癌症的免疫修饰剂结合起来.

关键词:

在CDK9中,CDK9是CDK9.埃尔克·埃尔克是什么意思克拉斯 (Kras) 是一个国家.补充激活是补充的激活.免疫抑制是一种免疫抑制.

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