TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers.
Cell Death Dis
; 15(4): 273, 2024 Apr 17.
Article
en En
| MEDLINE
| ID: mdl-38632238
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 TGFß 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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Apoptosis
/
Glioblastoma
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Proteína Serina-Treonina Quinasas de Interacción con Receptores
/
Glioma
Límite:
Humans
Idioma:
En
Revista:
Cell Death Dis
Año:
2024
Tipo del documento:
Article
País de afiliación:
Reino Unido