KRAS(G12D)-targeted therapy sensitivity depends on interferon signaling activation in pancreatic cancer.

Interferon signaling activation, especially IFN-β, determines sensitivity to KRAS G12D–targeted therapy in intrinsically resistant pancreatic cancer organoids, enabling synergistic drug combinations.

• Why it matters: Intrinsic resistance to KRAS G12D–targeted therapeutics in pancreatic cancer is poorly defined, limiting how to predict responders and design effective combination strategies.
• What they did: Integrated genomics, transcriptomics, and proteomics profiling across 242 patient-derived organoids and matched tumor tissues identified a KRAS G12D–mutant resistant subset linked to downregulated innate immune pathways; functional tests then modulated interferon signaling and assessed KRAS inhibitors (MRTX1133, HRS-4642, RMC-6236).
• The result: Suppressing interferon signaling induced resistance in sensitive models, while activating interferon signaling increased sensitivity in resistant models; combining IFN-β with KRAS inhibitors produced synergistic antitumor effects and linked attenuated sensitivity to sustained MYC activity with repressed interferon signaling.

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