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Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis

Sofya Tishina1,2, Alina Dahlhaus1,2, Marta Manik1,2

  • 1University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.

Nature Communications
|June 15, 2026
PubMed

Insights

Pancreatic cancer cells with KRAS mutations are primed for necroptosis by interferon signaling. Inhibiting caspase-8 triggers this cell death, offering a new therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with limited treatment options.
  • The KRAS oncogene is a key driver in PDAC development.
  • Understanding oncogene-induced cellular vulnerabilities is crucial for novel therapy development.

Purpose of the Study:

  • To investigate the mechanism by which KRAS drives PDAC.
  • To identify vulnerabilities in PDAC cells that can be therapeutically exploited.
  • To explore the role of the cGAS-STING-TBK1-IFN axis in PDAC.

Main Methods:

  • Genetically engineered mouse models of PDAC.
  • Analysis of caspase-8 and necroptosis-related gene expression.
  • Pharmacologic inhibition of caspase in PDAC models and patient-derived organoids.
  • Pan-cancer transcriptomic analysis.

Main Results:

  • KRAS activation induces a type I interferon (IFN) response via the cGAS-STING-TBK1 axis.
  • This IFN response primes PDAC cells for necroptosis.
  • Cancer cell-specific deletion of caspase-8 triggers necroptosis and eliminates precursor lesions.
  • Caspase inhibition sensitizes PDAC cells to necroptosis, reducing tumor burden.

Conclusions:

  • KRAS-driven IFN signaling creates a vulnerability to necroptosis in PDAC.
  • Targeting necroptosis via caspase inhibition is a promising therapeutic strategy for PDAC.
  • This mechanism has broader implications for IFN-activated cancers.

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