Prolonged KRAS-MAPK inhibition activates interferon signaling to promote cellular plasticity and uncover novel targets for combination therapy

KRAS-MAPK cascade inhibition shows promise for treating PDAC. However, resistance arises through secondary mutations that restore MAPK signaling and trigger epithelial-to-mesenchymal transition (EMT), key mechanisms of acquired resistance. Here, we show that human PDAC specimens and cells treated long-term with an ERK inhibitor exhibit upregulation of EMT and interferon signaling, with similar pattern also seen following prolonged KRAS inhibition in PDAC cells. Using the GeneRep-nSCORE framework, we identified TRIM22, an interferon-inducible E3 ubiquitin ligase, as a key mediator of EMT and resistance by promoting proteasomal degradation of IκBalpha and activating NF-κB signaling. Searching for druggable targets, we found TACSTD2 (TROP2), an NF-κB target gene upregulated after EMT. Combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan effectively suppressed growth of PDAC patient-derived xenografts. This study highlights TRIM22's role in linking interferon signaling with EMT and identifies TROP2 as a therapeutic vulnerability to overcome acquired resistance.