dc.contributor.author | Damhofer, H | |
dc.contributor.author | Tatar, T | |
dc.contributor.author | Southgate, B | |
dc.contributor.author | Scarneo, S | |
dc.contributor.author | Agger, K | |
dc.contributor.author | Shlyueva, D | |
dc.contributor.author | Uhrbom, L | |
dc.contributor.author | Morrison, GM | |
dc.contributor.author | Hughes, PF | |
dc.contributor.author | Haystead, T | |
dc.contributor.author | Pollard, SM | |
dc.contributor.author | Helin, K | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-07-03T12:43:54Z | |
dc.date.available | 2024-07-03T12:43:54Z | |
dc.date.issued | 2024-04-17 | |
dc.identifier | ARTN 273 | |
dc.identifier | 10.1038/s41419-024-06654-1 | |
dc.identifier.citation | Cell Death and Disease, 2024, 15 (4), pp. 273 - | en_US |
dc.identifier.issn | 2041-4889 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6284 | |
dc.identifier.eissn | 2041-4889 | |
dc.identifier.eissn | 2041-4889 | |
dc.identifier.doi | 10.1038/s41419-024-06654-1 | |
dc.identifier.doi | 10.1038/s41419-024-06654-1 | |
dc.description.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. | |
dc.format | Electronic | |
dc.format.extent | 273 - | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | SPRINGERNATURE | en_US |
dc.relation.ispartof | Cell Death and Disease | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Humans | |
dc.subject | Apoptosis | |
dc.subject | Cytokines | |
dc.subject | Glioblastoma | |
dc.subject | Glioma | |
dc.subject | MAP Kinase Kinase Kinases | |
dc.subject | Receptor-Interacting Protein Serine-Threonine Kinases | |
dc.subject | Signal Transduction | |
dc.subject | Transforming Growth Factor beta | |
dc.subject | Tumor Necrosis Factor-alpha | |
dc.title | TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2024-04-05 | |
dc.date.updated | 2024-07-03T12:43:06Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1038/s41419-024-06654-1 | en_US |
rioxxterms.licenseref.startdate | 2024-04-17 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38632238 | |
pubs.issue | 4 | |
pubs.organisational-group | ICR | |
pubs.publication-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41419-024-06654-1 | |
pubs.volume | 15 | |
icr.researchteam | CEO Office | en_US |
dc.contributor.icrauthor | Helin, Kristian | |
icr.provenance | Deposited by Mr Arek Surman on 2024-07-03. Deposit type is initial. No. of files: 1. Files: TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers.pdf | |