Prolonged KRAS-MAPK Inhibition Induces Interferon Signaling That Promotes Cell State Transition and Confers Therapeutic Vulnerabilities

Acquired resistance limits the therapeutic efficacy of KRAS-MAPK inhibitors in pancreatic ductal adenocarcinoma (PDAC). As transcriptional plasticity and epithelial-to-mesenchymal transition (EMT) have been implicated in resistance, we sought to study the molecular mechanisms driving these changes to uncover actionable vulnerabilities. Sustained KRAS-MAPK inhibition induced interferon (IFN) and NF-κB signaling and promoted cell state change mimicking an EMT state associated with drug resistance. Network analysis identified the IFN-inducible E3 ubiquitin Ligase TRIM22 as a central regulator of this response. Mechanistically, TRIM22 promoted proteasomal degradation of IκBα, resulting in sustained NF-κB and EMT program activation that coincided with a basal-like transcriptional cell state. TRIM22 expression was driven by IRF1 and IRF9 following relief of ERK-mediated transcriptional repression during pathway inhibition. EMT induction was accompanied by marked upregulation of TROP2 (TACSTD2), an NF-κB target gene enriched in basal-like PDAC cell states. Combining TROP2-directed antibody-drug conjugate sacituzumab govitecan with KRAS or ERK inhibitors significantly suppressed PDAC tumor growth in xenograft models. Overall, prolonged KRAS-MAPK inhibition activates an IFN-TRIM22-NF-κB axis that drives EMT and therapeutic resistance in PDAC, while revealing TROP2 as a clinically actionable vulnerability to overcome acquired resistance.

Significance: TRIM22 drives interferon-induced EMT and NF-κB-dependent TROP2 upregulation to drive resistance to KRAS-MAPK inhibition in pancreatic Cancer, which can be overcome by combining sacituzumab govitecan with KRAS-MAPK inhibitors.