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多重单细胞化学基因组学揭示了针对性治疗反应的激酶依赖性

José L McFaline-Figueroa¹, Sanjay Srivatsan², Andrew J Hill³

¹Department of Biomedical Engineering, Columbia University, New York, NY, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA.

|January 26, 2024

概括

这项研究引入了sci-Plex-Gene-by-Environment (sci-Plex-GxE),用于大规模的单细胞遗传和化学查. 它确定了组合疗法,以防止质母细胞瘤适应向治疗.

科学领域:

癌症生物学癌症生物学
基因组学就是基因组学.
药理学药理学是指药理学的学科.

背景情况:

化学遗传选提供了对癌症药物反应的见解,但缺乏基因水平的分子细节.
了解基因贡献对于优化向癌症治疗至关重要.

研究的目的:

开发和应用一个可扩展的平台,用于结合单细胞遗传和化学查.
阐明个体基因在质母细胞瘤对受体氨酸激酶通路抑制剂的反应中的作用.

主要方法:

引入sci-Plex-Gene-by-Environment (sci-Plex-GxE) 用于高通量选的方法. 这是一个非常好的方法.
在质母细胞细胞中检测了522个人类激酶在14121个基因环境组合中.
对1,052,205个单细胞转录组进行分析,以确定适应性信号通路.

主要成果:

识别了一种取决于MEK/MAPK的补偿适应信号的表达特征.
发现质母细胞细胞通过转录性变化适应向治疗.
揭示了有前途的组合疗法,包括使用CDC7/CDK9或NF-κB抑制剂的MEK抑制剂,以克服适应.

结论:

sci-Plex-GxE能够进行大规模,公正的查,以获得对药物反应的分子洞察力.
通过抑制补偿信号通路,可以增强向疗法.
针对MEK/MAPK和其他途径的组合疗法显示出治疗质母细胞瘤的潜力.

关键词:

适应性抵抗是一种适应性抵抗.化学遗传学化学遗传学化学基因组学化学基因组学结合的单细胞遗传和化学选.基因与环境的相互作用基因与环境的相互作用质母细胞瘤 (glioblastoma) 是一种激酶导向疗法是指向激酶的疗法.受体氨酸激酶信号传递受体一个单细胞的CRISPR屏幕.单细胞化学转录学单细胞化学转录学

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