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

Daniel Dorbin1,2, Juliannie Herrera1,2, Raven Davidson1,2

  • 1Department of Biochemistry, Medical College of Wisconsin and the LaBahn Pancreatic Cancer Program, Milwaukee, WI.

Biorxiv : the Preprint Server for Biology
|July 17, 2026
PubMed

Insights

KRAS allele-specific resistance to daraxonrasib involves distinct adaptive pathways. Targeting these pathways, like EGFR/RAS WT signaling, can improve outcomes in KRAS-mutant pancreatic cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS mutations are key drivers in pancreatic ductal adenocarcinoma (PDAC).
  • Understanding adaptive resistance mechanisms to targeted therapies is crucial for improving patient outcomes.
  • RAS allele-specific network dynamics present unique challenges for therapeutic intervention.

Purpose of the Study:

  • To investigate the allele-specific resistance mechanisms to the RAS(ON) inhibitor daraxonrasib in KRAS G12D and KRAS G12R mutant PDAC.
  • To identify therapeutic strategies to overcome adaptive resistance based on distinct RAS allele-driven pathways.
  • To evaluate the clinical efficacy of targeted therapies in a KRAS G12R PDAC patient with acquired resistance.

Main Methods:

  • Utilized daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor.
  • Compared resistance mechanisms in KRAS G12D and KRAS G12R PDAC cell lines.
  • Assessed signaling pathway activation (EGFR/RAS WT-GTP) and protein expression (cyclophilin A).
  • Employed rapid 3D-bioprinted patient-derived toroid modeling for therapy prediction.
  • Analyzed clinical data from a KRAS G12R PDAC patient.

Main Results:

  • Daraxonrasib resistance in KRAS G12R PDAC cells predominantly utilized EGFR/RAS WT-GTP signaling.
  • Resistance in KRAS G12D PDAC cells involved retained KRAS G12D-GTP signaling and decreased cyclophilin A (CypA).
  • The shift to EGFR/RAS WT signaling in KRAS G12R conferred sensitivity to trametinib.
  • Patient-derived toroid modeling predicted sensitivity to trametinib-based combination therapy.
  • A KRAS G12R PDAC patient achieved 40 months of overall survival with sixth-line trametinib combination therapy.

Conclusions:

  • RAS allele-specific network topology dictates adaptive resistance landscapes in PDAC.
  • Downregulation of CypA in KRAS G12D and reliance on EGFR/RAS WT in KRAS G12R are distinct resistance routes.
  • Rapid patient-derived toroids can guide effective targeted therapy selection for advanced PDAC.
  • Targeted combination therapies can achieve significant and durable responses in metastatic PDAC.

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