KRASG12D-targeted therapy sensitivity depends on interferon signaling activation in pancreatic cancer.

KRASG12D is a predominant driver in pancreatic cancer, yet the basis of intrinsic resistance to KRASG12D-targeted therapy remains poorly defined. Integrated genomics, transcriptomics, and proteomics profiling across 242 patient-derived organoids (PDOs) and matched tumor tissues reveals a KRASG12D-mutant subset intrinsically resistant to KRASG12D-targeted therapeutics, characterized by marked downregulation of innate immune signaling pathways. Functional validation demonstrates that suppressing interferon signaling in sensitive models induces resistance, whereas activation of interferon signaling, particularly interferon beta (IFN-β), increases sensitivity in resistant models. Combining IFN-β with KRAS inhibitors (MRTX1133, HRS-4642, and RMC-6236) exhibits synergistic antitumor effects in intrinsically resistant pancreatic cancer. Mechanistically, sustained MYC activity is associated with attenuated sensitivity to KRAS inhibition and correlates with repressed interferon signaling, suggesting a potential role in promoting intrinsic resistance. These findings identify interferon signaling as a candidate determinant of KRAS-targeted therapy response and support interferon-based combinations as a potential strategy for intrinsically resistant pancreatic cancer.