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Allele-Specific Mechanisms Guide Salvage Therapy to Overcome Daraxonrasib Resistance in Pancreatic Cancer

Year: 2026
Type: article
Abstract: Clinical-grade RAS inhibitors raise an unresolved question about whether KRAS alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multiselective RAS(ON) inhibitor, we compared resistance mechanisms between KRASG12D and KRASG12R, mutants with fundamentally different RAS network dynamics. Daraxonrasib inhibited mutant KRAS primarily through steric occlusion of effector binding while engaging wild-type RAS (RASWT) only modestly (∼20%). KRASG12R was marked by its inability to transactivate RASWT, and daraxonrasib-resistant KRASG12R pancreatic ductal adenocarcinoma (PDAC) cells utilized EGFR/RASWT-GTP signaling as the dominant adaptive route. In contrast, KRASG12D resistance arose through retained KRASG12D-GTP signaling, with a decrease in cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRASG12R dependence to EGFR/RASWT dependence conferred sensitivity to trametinib. As clinical confirmation, a patient with KRASG12R PDAC who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RASWT activation, and rapid 3D-bioprinted patient-derived tumoroid modeling predicted sensitivity to trametinib-based combination therapy. Despite 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, and this patient ultimately achieved 40 months of overall survival, far exceeding the 8 to 12 months 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. SIGNIFICANCE: Daraxonrasib resistance emerges through allele-specific routes, with CypA being downregulated in KRASG12D and reliance on EGFR/RASWT in KRASG12R cancer cells, informing mechanism-based therapeutic strategies for patients who progress on RAS inhibitors.
DOI: 10.1158/0008-5472.can-26-1181
Authors: Daniel Dorbin, Juliannie Herrera, Raven Davidson, Naveen Kumar Chandrashekar, Gabrielle Scheuber, Priyanga Jayakrishnan, Christabelle Rajesh, Grayson Johnson, Jason Yuan, Matthew A. 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
Institutions: Medical College of Wisconsin, Medical University of South Carolina, MUSC Hollings Cancer Center, Thomas Jefferson University, Sidney Kimmel Cancer Center, The Ohio State University Wexner Medical Center
Language: English
Open Access status: hybrid
Funders: American Cancer Society, Concern Foundation, Pancreatic Cancer Action Network, Medical College of Wisconsin, National Institutes of Health, National Institute of General Medical Sciences
OpenAlex ID: W7204466430
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