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野生型RAS信号传递是RAS突变癌症中必不可少的治疗标

Nancy E Sealover¹, Bridget A Finniff¹, Jacob M Hughes¹

¹Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.

Science signaling

|September 16, 2025

概括

野生型RAS蛋白通过激活突变RAS未准的途径来支持癌症生长. 针对突变型和野生型RAS的组合疗法对治疗RAS突变型癌症有很大的希望.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
癌症遗传学癌症遗传学

背景情况:

突变的RAS蛋白质是致癌转变和癌症进展的关键驱动因素.
包括RAF-MEK-ERK和PI3K-AKT在内的RAS效应因子通路由RAS家族成员不同的方式参与.
有效治疗RAS突变癌症往往需要联合抑制这些作用因子通路.

研究的目的:

阐明野生型RAS蛋白在支持由突变RAS驱动的瘤信号传递中的作用.
调查共同向突变RAS及其支持野生型RAS家族成员的治疗潜力.
确定在RAS突变癌症中实现协同细胞毒性的特定抑制剂组合.

主要方法:

在癌细胞中研究了突变型和野生型RAS家族成员之间的信号相互作用.
使用针对突变RAS蛋白及其下游效应因子通路的特定抑制剂 (例如MEK,PI3K抑制剂,法纳西转移酶抑制剂蒂法尼布).
在癌细胞系和缺乏RAS蛋白的转基因小鼠胚胎纤维细胞 (MEFs) 中评估了协同作用的细胞毒性.

主要成果:

野生型RAS蛋白为突变的RAS通路提供必要的信号支持.
野生型KRAS和NRAS在HRAS突变细胞中促进RAF-MEK-ERK信号传递;野生型HRAS和NRAS在KRAS突变细胞中促进PI3K-AKT信号传递.
结合抑制突变RAS和依赖于野生类型RAS表达的不良参与的效应因子通路,导致了协同性细胞毒性.

结论:

野生型RAS家族成员在维持突变RAS驱动的瘤信号传递方面发挥着关键作用.
针对野生型RAS蛋白与突变RAS抑制剂结合,代表了对RAS突变癌症的有前途的治疗策略.
对野生类型RAS表达的依赖强调了其作为潜在的治疗共同目标的重要性.

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