TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers.
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Embargo End Date
ICR Authors
Authors
Damhofer, H
Tatar, T
Southgate, B
Scarneo, S
Agger, K
Shlyueva, D
Uhrbom, L
Morrison, GM
Hughes, PF
Haystead, T
Pollard, SM
Helin, K
Tatar, T
Southgate, B
Scarneo, S
Agger, K
Shlyueva, D
Uhrbom, L
Morrison, GM
Hughes, PF
Haystead, T
Pollard, SM
Helin, K
Document Type
Journal Article
Date
2024-04-17
Date Accepted
2024-04-05
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.
Citation
Cell Death and Disease, 2024, 15 (4), pp. 273 -
Source Title
Cell Death and Disease
Publisher
SPRINGERNATURE
ISSN
2041-4889
eISSN
2041-4889
2041-4889
2041-4889
Collections
Research Team
CEO Office