Allele-Specific Mechanisms Guide Salvage Therapy to Overcome Daraxonrasib Resistance 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 KRASG12D and KRASG12R, mutants with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRASMUT primarily through steric occlusion of effector binding, while engaging RASWT only modestly (~20%). KRASG12R was marked by its inability to transactivate RASWT, and daraxonrasib resistant KRASG12R 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 of 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 KRASG12R PDAC patient 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 8-12 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.

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Journal
Cancer Research
Published
2026-08-27
DOI
https://doi.org/10.1158/0008-5472.can-26-1181
Primary Topic
Signaling Pathways in Disease
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Nikki K. Lytle, Francis C. Peterson, Mandana Kamgar, Anikó Szabó et al.
Cancer Research
Signaling Pathways in Disease
article

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

Nikki K. Lytle, Francis C. Peterson, Mandana Kamgar, Anikó Szabó, Susan Tsai, Forough Azam Sayahpour, Priyanga Jayakrishnan, Razelle Kurzrock, Christabelle Rajesh, Thomas McFall, G. Aaron Hobbs, Eugene Ke, Yongwoo David Seo, Douglas B. Evans, Naveenkumar Chandrashekar, Mahmoud Ali, Brian F. Volkman, John F. Langenheim, Charles Messerly, Daniel Dorbin, Jacquelyn Wittmann, Juliannie Herrera, Raven Davidson, Mohammed Aldakkak, Grayson Johnson, Nathan L. Atallah, Gabrielle Scheuber, Jason Yuan, Matthew A. Sochor
article en

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 KRASG12D and KRASG12R, mutants with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRASMUT primarily through steric occlusion of effector binding, while engaging RASWT only modestly (~20%). KRASG12R was marked by its inability to transactivate RASWT, and daraxonrasib resistant KRASG12R 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 of 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 KRASG12R PDAC patient 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 8-12 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.

Cancer Research
Thomas Jefferson University (US), Medical University of South Carolina (US), Medical College of Wisconsin (US), The Ohio State University Wexner Medical Center (US), NanoAffix Science (United States) (US), University of Nebraska Medical Center (US)
National Institute of General Medical Sciences
Openalex Percentile: Top 17%
Signaling Pathways in Disease
DOIOpen Access PDFOpenAlex
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