TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers Journal Article
| Authors: | Damhofer, H.; Tatar, T.; Southgate, B.; Scarneo, S.; Agger, K.; Shlyueva, D.; Uhrbom, L.; Morrison, G. M.; Hughes, P. F.; Haystead, T.; Pollard, S. M.; Helin, K. |
| Article Title: | TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers |
| 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. © The Author(s) 2024. |
| Keywords: | signal transduction; glioma; metabolism; apoptosis; transforming growth factor beta; cytokine; cytokines; tumor necrosis factor-alpha; glioblastoma; tumor necrosis factor; map kinase kinase kinases; mitogen activated protein kinase kinase kinase; humans; human; receptor interacting protein serine threonine kinase; receptor-interacting protein serine-threonine kinases; ripk1 protein, human |
| Journal Title: | Cell Death & Disease |
| Volume: | 15 |
| ISSN: | 2041-4889 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-04-17 |
| Start Page: | 273 |
| Language: | English |
| DOI: | 10.1038/s41419-024-06654-1 |
| PUBMED: | 38632238 |
| PROVIDER: | scopus |
| PMCID: | PMC11024179 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
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