Details

Autor(en) / Beteiligte

• Damhofer, Helene
• Tatar, Tülin
• Southgate, Benjamin
• Scarneo, Scott
• Agger, Karl
• Shlyueva, Daria
• Uhrbom, Lene
• Morrison, Gillian M
• Hughes, Philip F
• Haystead, Timothy
• Pollard, Steven M
• Helin, Kristian

Titel

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

Ist Teil von

• Cell death & disease, 2024-04, Vol.15 (4), p.273-273

Ort / Verlag

England: Springer Nature B.V

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.