A classical epithelial state drives acute resistance to KRAS inhibition in pancreas cancer. A classical epithelial state drives acute resistance to KRAS inhibition in pancreas cancer

Intra-tumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor-induced enrichment of the classical state. Lineage-tracing identifies these enriched classical PDAC cells to be a reservoir for disease relapse. Genetic ablation of the classical cell-state is synergistic with KRAS inhibition, providing a pre-clinical proof-of-concept for this therapeutic strategy. Our findings motivate combining classical-state directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer. Overall design: NSG mice bearing orthotopic KP mouse cell line allografts (pancreatic cancer) or human subcutaneous patient-derived-xenografts (PDXs) of pancreatic cancer were administered MRTX1133 at 30 mg/kg b.i.d. vs. vehicle. Mouse PDAC tumors were treated for 7 days. PDX experiments were treated for 10-14 days. Orthotopically transplanted and PDX tumors were dissociated into single-cell suspensions and FACS sorted for tumor cells for single-cell RNA sequencing. Each dataset represents a tumor type (mouse KP tumor, or human PDX#1-3 treated with either vehicle or MRTX1133). Biological replicates with the same treatment were combined into one lane with HTO antibodies. Vehicle-treated and MRTX1133-treated tumors for each experiment were compared.