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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月15日

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  • Sofya Tishina,
  • Alina Dahlhaus,
  • Marta Manik,
  • Lejla Mulalic,
  • Janine Murr,
  • Michael Kotliar,
  • Hassan Rakhsh-Khorshid,
  • Myrto Kostopoulou,
  • Florian Hocher,
  • Jenny Stroh,
  • Julia Beck,
  • Riley M. Williams,
  • Gülce G. Balta,
  • Fanyu Liu,
  • Ali T. Abdallah,
  • Christina M. Bebber,
  • Moritz Reese,
  • Jonathan K. M. Lim,
  • Alexander Quaas,
  • Johannes Brägelmann,
  • Manolis Pasparakis,
  • Filippo Beleggia,
  • Siddharth Balachandran,
  • Anna Trauzold,
  • Gianmaria Liccardi,
  • Igor Astsaturov,
  • Maximilian Reichert,
  • Ariadne Androulidaki,
  • Silvia von Karstedt

摘要

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.