Multiplex single-cell chemical genomics reveals the kinase dependence of the response to targeted therapy
Multiplex single-cell chemical genomics reveals the kinase dependence of the response to targeted therapy
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DOI：
10.1016/j.xgen.2023.100487
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发表时间：
2024-02-14
期刊：
影响因子：
--
通讯作者：
Trapnell，Cole
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文献类型：
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作者：
McFaline-Figueroa，Jose L.;Srivatsan，Sanjay;Trapnell，Cole
化学基因筛选是一种强大的工具，可以探索癌细胞对药物的反应是如何由它们的突变形成的，但它们缺乏单个基因对暴露反应的分子观点。在这里，我们提出了sci-Plex-Gene-by-Environment (sci-Plex-GxE)，这是一个大规模联合单细胞遗传和化学筛选的平台。通过确定522种人类激酶对胶质母细胞瘤对不同药物的反应的贡献，我们强调了大规模，无偏倚筛选的优势，这些药物旨在消除受体酪氨酸激酶途径的信号传导。总共，我们在1,052,205个单细胞转录组中探测了14,121个基因-环境组合。我们发现了一个代偿性自适应信号的表达特征，以MEK/ mapk依赖的方式调节。进一步的分析表明，包括双MEK和CDC7/CDK9或核因子κB （NF-κB）抑制剂在内的有希望的联合治疗是阻止胶质母细胞瘤对靶向治疗的转录适应的有效手段。
Chemical genetic screens are a powerful tool for exploring how cancer cells' response to drugs is shaped by their mutations, yet they lack a molecular view of the contribution of individual genes to the response to exposure. Here, we present sci-Plex-Gene-by-Environment (sci-Plex-GxE), a platform for combined single-cell genetic and chemical screening at scale. We highlight the advantages of large-scale, unbiased screening by defining the contribution of each of 522 human kinases to the response of glioblastoma to different drugs designed to abrogate signaling from the receptor tyrosine kinase pathway. In total, we probed 14,121 gene-by-environment combinations across 1,052,205 single-cell transcriptomes. We identify an expression signature characteristic of compensatory adaptive signaling regulated in a MEK/MAPK-dependent manner. Further analyses aimed at preventing adaptation revealed promising combination therapies, including dual MEK and CDC7/CDK9 or nuclear factor κB (NF-κB) inhibitors, as potent means of preventing transcriptional adaptation of glioblastoma to targeted therapy.