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TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers
Inst Canc Res, Div Canc Biol, London, England.;Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10065 USA.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..ORCID-id: 0000-0003-4459-7534
Inst Canc Res, Div Canc Biol, London, England.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
Univ Edinburgh, Ctr Regenerat Med, Edinburgh, Scotland..
Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA.;EydisBio Inc, Durham, NC USA..
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2024 (engelsk)Inngår i: Cell Death and Disease, E-ISSN 2041-4889, Vol. 15, artikkel-id 273Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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 IFN gamma 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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Springer Nature, 2024. Vol. 15, artikkel-id 273
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URN: urn:nbn:se:uu:diva-527501DOI: 10.1038/s41419-024-06654-1ISI: 001205160000003PubMedID: 38632238OAI: oai:DiVA.org:uu-527501DiVA, id: diva2:1855867
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EU, Horizon 2020, 749362Tilgjengelig fra: 2024-05-03 Laget: 2024-05-03 Sist oppdatert: 2024-07-04bibliografisk kontrollert

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