Journal Article

DKFZ-2026-01439

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis.

Tishina, S. ; Dahlhaus, A. ; Manik, M. ; Mulalic, L. ; Murr, J. ; Kotliar, M. ; Rakhsh-Khorshid, H. ; Kostopoulou, M. ; Hocher, F. ; Stroh, J. ; Beck, J. ; Williams, R. M. ; Balta, G. G. ; Liu, F. ; Abdallah, A. T. ; Bebber, C. M. ; Reese, M. ; Lim, J. K. M. ; Quaas, A. ; Brägelmann, J. ; Pasparakis, M. ; Beleggia, F. ; Balachandran, S. ; Trauzold, A. ; Liccardi, G. ; Astsaturov, I. ; Reichert, M.DKFZ* ; Androulidaki, A. ; von Karstedt, S.

2026
Springer Nature [London]

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death within this decade. Here, we show that its major driver oncogene KRAS activates the cGAS-STING-TBK1 axis, inducing a type I interferon (IFN) response that primes PDAC cells for necroptosis. Using genetically engineered mouse models, we find that cancer cell-specific deletion of caspase-8 is sufficient to trigger necroptotic cell death, eliminating most pancreatic precursor lesions. Mechanistically, KRAS-driven IFN signalling induces ISGF3-dependent expression of necroptosis-related interferon-stimulated genes, including MLKL. This renders PDAC cells selectively vulnerable to necroptosis upon caspase-8 inhibition. Therapeutically, pharmacologic caspase inhibition reduces tumour burden in aggressive PDAC models and human patient-derived organoids. A pan-cancer transcriptomic analysis links necroptosis gene expression with Ras pathway activity and IFN signatures across multiple tumour types. These findings reveal a KRAS-induced IFN program that sensitises tumour cells to necroptosis, highlighting a therapeutic vulnerability in PDAC with broader relevance across IFN-activated cancers.

Keyword(s): Animals (MeSH) ; Necroptosis: genetics (MeSH) ; Pancreatic Neoplasms: genetics (MeSH) ; Pancreatic Neoplasms: metabolism (MeSH) ; Pancreatic Neoplasms: pathology (MeSH) ; Interferon Type I: metabolism (MeSH) ; Humans (MeSH) ; Proto-Oncogene Proteins p21(ras): genetics (MeSH) ; Proto-Oncogene Proteins p21(ras): metabolism (MeSH) ; Carcinoma, Pancreatic Ductal: genetics (MeSH) ; Carcinoma, Pancreatic Ductal: pathology (MeSH) ; Carcinoma, Pancreatic Ductal: metabolism (MeSH) ; Mice (MeSH) ; Signal Transduction (MeSH) ; Caspase 8: metabolism (MeSH) ; Caspase 8: genetics (MeSH) ; Cell Line, Tumor (MeSH) ; cGAS-STING Signaling Pathway (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Protein Serine-Threonine Kinases: metabolism (MeSH) ; Interferon Type I ; Proto-Oncogene Proteins p21(ras) ; Caspase 8 ; Hras protein, mouse ; KRAS protein, human ; Protein Serine-Threonine Kinases

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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