Oncogenic KRAS-induces necroptotic priming of pancreatic neoplasia

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality. PDAC expresses high levels of caspase 8, a central enzyme controlling various types of regulated cell death. Here, using genetically engineered mouse models we find that oncogenic KRAS-driven neoplastic transformation induces a transcriptional state of necroptotic priming, but necroptosis itself is counter selected against through co-upregulation of caspase 8. Mechanistically, expression of the driver oncogene KRAS induced a STING-dependent type I interferon (IFN) response resulting in upregulation of the necroptosis pathway leading to necroptotic priming. High caspase 8 expression in precursor lesions was a result of co-selection to prevent necroptosis. Hence, genetic or pharmacological targeting of caspase 8 was therapeutically highly efficacious in models of genetically engineered PDAC in vivo . These results identify type I IFN-induced necroptotic priming as synthetic lethality of KRAS-driven PDAC and show that targeting it has therapeutic benefit in this incurable malignancy.