裂谷1
癌症研究
坏死性下垂
肿瘤坏死因子α
免疫系统
自分泌信号
生物
细胞凋亡
激酶
程序性细胞死亡
细胞生物学
免疫学
细胞培养
生物化学
遗传学
作者
Helene Damhofer,Tülin Tatar,Benjamin Southgate,Scott Scarneo,Karl Agger,Daria Shlyueva,Lene Uhrbom,Gillian Morrison,Philip F. Hughes,Timothy A.J. Haystead,Steven M. Pollard,Kristian Helin
标识
DOI:10.1038/s41419-024-06654-1
摘要
Abstract Poor survival and lack of treatment response in glioblastoma (GBM) is attributed to the persistence of glioma stem cells (GSCs). To identify novel therapeutic approaches, we performed CRISPR/Cas9 knockout screens and discovered TGFβ activated kinase (TAK1) as a selective survival factor in a significant fraction of GSCs. Loss of TAK1 kinase activity results in RIPK1-dependent apoptosis via Caspase-8/FADD complex activation, dependent on autocrine TNFα ligand production and constitutive TNFR signaling. We identify a transcriptional signature associated with immune activation and the mesenchymal GBM subtype to be a characteristic of cancer cells sensitive to TAK1 perturbation and employ this signature to accurately predict sensitivity to the TAK1 kinase inhibitor HS-276. In addition, exposure to pro-inflammatory cytokines IFNγ and TNFα can sensitize resistant GSCs to TAK1 inhibition. Our findings reveal dependency on TAK1 kinase activity as a novel vulnerability in immune-activated cancers, including mesenchymal GBMs that can be exploited therapeutically.
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