Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer

Clinical-grade RAS inhibitors raise an unresolved question as to whether KRAS-alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor, we compared resistance mechanisms between KRAS G12D and KRAS G12R, alleles with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRAS ^MUT primarily through steric occlusion of effector binding, while engaging RAS ^WT only modestly (∼20%). KRAS ^G12R is marked by its inability to transactivate RAS ^WT , and it was observed that daraxonrasib resistant KRAS ^G12R PDAC cells utilize EGFR/RAS ^WT -GTP signaling as the dominant adaptive route. In contrast, KRAS ^G12D resistance arose through retained KRAS ^G12D -GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRAS ^G12R dependence to the EGFR/RAS ^WT conferred sensitivity to trametinib. We confirmed this clinically: a KRAS ^G12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RAS ^WT activation, and rapid 3D-bioprinted patient-derived toroid modeling predicted sensitivity to trametinib-based combination therapy. Given the aggressive disease trajectory and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control. This patient ultimately achieved 40 months of overall survival, far exceeding the 8-12 month median for metastatic PDAC. Collectively, these data establish a framework in which allele-specific RAS network topology dictates the adaptive resistance landscape, enabling rational selection of targeted therapies with meaningful clinical benefit in metastatic PDAC.

Daraxonrasib resistance mechanisms have allele-specific routes: CypA becomes downregulated in KRAS ^G12D and reliance on EGFR/RAS ^WT in KRAS ^G12R . Rapid patient-derived toroids identified sixth-line targeted therapy strategies with an overall survival of 40 months.