Abstract B060: From Resistance to Rescue: Allele-Informed Salvage Therapy Following Daraxonrasib Resitance in Pancreatic Cancer
Thomas McFall, Daniel Dorbin, Juliannie Herrera, Raven Davidson, Douglas B. Evans, Susan Tsai, K. Nikki, Y. David Seo, Razelle Kurzrock, G. Aaron Hobbs, Mandana KamgarAbstract
Background:
Clinical-grade RAS(ON) inhibitors have transformed treatment of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC), but acquired resistance is universal and post-progression treatment selection remains empiric. Whether specific KRAS alleles impose distinct constraints on the adaptive resistance network, and whether these constraints can be exploited therapeutically, is unresolved.
Methods:
We compared resistance mechanisms to daraxonrasib, a multi-selective RAS(ON) inhibitor, between isogenic PDAC models harboring KRAS G12D versus KRAS G12R, alleles with divergent RAS network dynamics. Signaling was characterized by RAS activity assays, biochemical profiling of the mutant/wild-type RAS ratio, and cyclophilin A (CypA) expression. Findings were extended to a KRAS G12R PDAC patient who progressed after 10 months of daraxonrasib, using biochemical profiling of resected tumor and rapid 3D-bioprinted patient-derived toroids to model candidate salvage regimens.
Results:
Daraxonrasib inhibited mutant KRAS primarily through steric occlusion of effector binding while engaging wild-type RAS only modestly (∼20%). KRAS G12R was unable to transactivate wild-type RAS, and daraxonrasib-resistant KRAS G12R cells instead adopted EGFR/wild-type RAS-GTP signaling as the dominant adaptive route. In contrast, KRAS G12D resistance arose through retained mutant KRAS-GTP signaling accompanied by loss of CypA, the binding partner required for daraxonrasib activity. The shift toward EGFR/wild-type RAS dependence in the G12R setting conferred sensitivity to trametinib. Consistent with the preclinical data, the patient's resected tumor showed intratumoral EGFR/wild-type RAS activation at progression, and patient-derived toroids predicted sensitivity to trametinib-based combination therapy. Despite an aggressive disease course 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 the patient ultimately achieved 40 months of overall survival, substantially exceeding the 8–12 month median for metastatic PDAC.
Conclusions:
KRAS allele identity dictates the topology of the adaptive resistance network following RAS(ON) inhibitor therapy, generating allele-specific and therapeutically actionable vulnerabilities. These data establish a mechanistic and translational framework, validated with a rapid patient-derived toroid platform, for rational, mechanism-informed salvage therapy selection in patients who progress on RAS inhibitors.
Citation Format:
Thomas McFall, Daniel Dorbin, Juliannie Herrera, Raven Davidson, Douglas B. Evans, Susan Tsai, K. Nikki, Y. David Seo, Razelle Kurzrock, G. Aaron Hobbs, Mandana Kamgar. From Resistance to Rescue: Allele-Informed Salvage Therapy Following Daraxonrasib Resitance in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B060.