Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis PMID: 42297776

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2026 Jun 15;17(1):5288. doi: 10.1038/s41467-026-73189-8.

Sofya Tishina ¹ ² , Alina Dahlhaus ¹ ² , Marta Manik ¹ ² , Lejla Mulalic ¹ ² , Janine Murr ³ ⁴ , Michael Kotliar ⁵ , Hassan Rakhsh-Khorshid ⁶ , Myrto Kostopoulou ¹ ² , Florian Hocher ⁷ , Jenny Stroh ¹ ² , Julia Beck ¹ ² , Riley M Williams ⁸ , Gülce G Balta ¹ ² , Fanyu Liu ¹ ² , Ali T Abdallah ² ⁹ , Christina M Bebber ¹ ² , Moritz Reese ¹ ² , Jonathan K M Lim ¹⁰ , Alexander Quaas ¹¹ , Johannes Brägelmann ¹ ² ¹² ¹³ , Manolis Pasparakis ² ¹³ ¹⁴ , Filippo Beleggia ¹ ² , Siddharth Balachandran ⁸ , Anna Trauzold ⁷ ¹⁵ , Gianmaria Liccardi ⁶ , Igor Astsaturov ¹⁶ , Maximilian Reichert ³ ⁵ ¹⁷ ¹⁸ , Ariadne Androulidaki ¹ ² , Silvia von Karstedt ¹⁹ ²⁰ ²¹

Affiliations

1. University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.
2. CECAD Cluster of Excellence, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
3. Translational Pancreatic Cancer Research Centre, TUM School of Medicine and Health, Department of Clinical Medicine - Clinical Department for Internal Medicine II, TUM University Hospital, Technical University of Munich, Munich, Germany.
4. Centre for Organoid Systems (COS), Technical University Munich (TUM), Garching, Germany.
5. Cincinnati Children's Hospital Medical Center, Division of Allergy and Immunology, Cincinnati, OH, USA.
6. University of Cologne, Faculty of Medicine and University Hospital Cologne, Centre for Biochemistry, Cologne, Germany.
7. University of Kiel, Institute for Experimental Cancer Research, Kiel, Germany.
8. Fox Chase Cancer Center, Cancer Signaling and Microenvironment Program, Philadelphia, PA, USA.
9. Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Cologne, Germany.
10. Heinrich Heine University, Medical Faculty and University Hospital Düsseldorf, Institute of Neuropathology, Düsseldorf, Germany.
11. University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany.
12. University Hospital Cologne, Mildred Scheel School of Oncology, Cologne, Germany.
13. University Hospital Cologne, Centre for Molecular Medicine Cologne (CMMC), Cologne, Germany.
14. University of Cologne, Institute for Genetics, Cologne, Germany.
15. University Hospital Schleswig-Holstein (UKSH), Department of Gynecology and Obstetrics, Campus Kiel, Kiel, Germany.
16. Fox Chase Cancer Center, Molecular Therapeutics Program, Philadelphia, PA, USA.
17. German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany.
18. Bavarian Cancer Research Centre (BZKF), Munich, Germany.
19. University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany. [email protected].
20. CECAD Cluster of Excellence, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. [email protected].
21. University Hospital Cologne, Centre for Molecular Medicine Cologne (CMMC), Cologne, Germany. [email protected].

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.