Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis - PubMed
3 hours ago
- #KRAS
- #pancreatic cancer
- #necroptosis
- Oncogenic KRAS activates the cGAS-STING-TBK1 axis, inducing a type I interferon (IFN) response in pancreatic ductal adenocarcinoma (PDAC) cells.
- This IFN signaling primes PDAC cells for necroptosis by upregulating interferon-stimulated genes like MLKL, making them vulnerable to caspase-8 inhibition.
- In genetically engineered mouse models, deleting caspase-8 in cancer cells triggers necroptotic cell death, eliminating most pancreatic precursor lesions.
- Pharmacologic caspase inhibition reduces tumor burden in aggressive PDAC models and human patient-derived organoids, indicating therapeutic potential.
- A pan-cancer analysis links necroptosis gene expression with Ras pathway activity and IFN signatures across multiple tumor types, suggesting broader relevance.