Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer
Year: 2026
Type: preprint
Abstract: ABSTRACT 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. STATEMENT OF SIGNIFICANCE 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.
Authors: Daniel Dorbin, Juliannie Herrera, Raven Davidson, Naveen Kumar Chandrashekar, Gabrielle Scheuber, Priyanga Jayakrishnan, Christabelle Rajesh, Grayson Johnson, Jason Yuan, Matthew Sochor, John F. Langenheim, Mohammed Aldakkak, Charles Messerly, Jacquelyn Wittmann, Aniko Szabo, Forough Azam Sayahpour, Nathan L. Atallah, Francis C. Peterson, Brian F. Volkman, Mahmoud Ali, Eugene Ke, Douglas B. Evans, Susan Tsai, Nikki K. Lytle, Y. David Seo, Razelle Kurzrock, G. Aaron Hobbs, Mandana Kamgar, Thomas McFall
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7167916693