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在KRAS突变的大脑动脉静脉形缺陷的双MAPK/VEGF抑制

Ryan M Naylor¹, Yasuhito Ueki^1,2, Fatmah R Alsereidi^1,3

¹1Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota.

Journal of neurosurgery

|October 31, 2025

概括

激活KRAS突变导致大脑动脉静脉形形 (bAVMs) 和破裂. 双抑制MAPK和VEGF通路为KRAS突变的bAVM提供了一个有希望的治疗策略,在小鼠模型中显著改善了生存率.

科学领域:

神经科学是一个神经科学.
遗传学遗传学是一个
血管生物学血管生物学

背景情况:

大脑动脉静脉形形 (bAVMs) 是一种罕见的,严重的脑血管疾病.
在零星的bAVM中经常发现激活KRAS突变,但它们在疾病发病和临床影响中的作用尚不清楚.

研究的目的:

研究一种针对出血性bAVM的新型治疗策略.
评估双重抑制的基因激活蛋白激酶 (MAPK) 和血管内皮生长因子 (VEGF) 途径.
为了利用一个具有可定位KRASG12V-GFP转基因的工程小鼠模型.

主要方法:

在小鼠中,AAV-BR1-CAG载体将KRASG12V-GFP转基因传递到大脑内皮细胞中.
对bAVM形成,脑内出血 (ICH) 和生存率的剂量依赖性评估.
用特拉美丁尼布 (MEK 抑制剂) 或RMC-7977 (RAS 抑制剂) 治疗出血性bAVM,有或没有抗VEGF抗体.

主要成果:

KRASG12V-GFP过度表达以剂量依赖的方式诱导了bAVMs,与增加的ICH和减少的存活率相关.
特拉美替尼布显示适度的生存益处;单独RMC-7977没有显著的影响.
RAS/MEK抑制剂与抗VEGF抗体的联合治疗显著延长了生存时间,特别是RMC-7977加抗VEGF.

结论:

大脑内皮细胞中的KRAS突变可能会促进bAVM的形成和破裂.
同时抑制MAPK和VEGF通路对于KRAS突变的bAVMs来说是一个有前途的治疗策略.

关键词:

克拉斯 (Kras) 是一个国家.血管新生抑制剂血管新生抑制剂大脑动脉静脉形形线素激活蛋白激酶信号通路的信号通路.血管疾病血管疾病

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