TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers.

Autor: Damhofer H; Division of Cancer Biology, The Institute of Cancer Research, London, UK.; Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark., Tatar T; Division of Cancer Biology, The Institute of Cancer Research, London, UK.; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark., Southgate B; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK., Scarneo S; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.; EydisBio Inc., Durham, NC, USA., Agger K; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark., Shlyueva D; Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark., Uhrbom L; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden., Morrison GM; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK., Hughes PF; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.; EydisBio Inc., Durham, NC, USA., Haystead T; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.; EydisBio Inc., Durham, NC, USA., Pollard SM; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK., Helin K; Division of Cancer Biology, The Institute of Cancer Research, London, UK. kristian.helin@icr.ac.uk.; Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. kristian.helin@icr.ac.uk.; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. kristian.helin@icr.ac.uk.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Apr 17; Vol. 15 (4), pp. 273. Date of Electronic Publication: 2024 Apr 17.
DOI: 10.1038/s41419-024-06654-1
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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