TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers.
Date
2024-04-17ICR Author
Author
Damhofer, H
Tatar, T
Southgate, B
Scarneo, S
Agger, K
Shlyueva, D
Uhrbom, L
Morrison, GM
Hughes, PF
Haystead, T
Pollard, SM
Helin, K
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Apoptosis
Cytokines
Glioblastoma
Glioma
MAP Kinase Kinase Kinases
Receptor-Interacting Protein Serine-Threonine Kinases
Signal Transduction
Transforming Growth Factor beta
Tumor Necrosis Factor-alpha
Research team
CEO Office
Language
eng
Date accepted
2024-04-05
License start date
2024-04-17
Citation
Cell Death and Disease, 2024, 15 (4), pp. 273 -
Publisher
SPRINGERNATURE