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

KRASG12R pancreatic cancer cells develop resistance to daraxonrasib via EGFR/RASWT signaling, enabling effective trametinib-based therapy and extending patient survival to 40 months.

• Why it matters: Understanding how different KRAS mutations influence resistance mechanisms is crucial for optimizing targeted therapies in pancreatic ductal adenocarcinoma, which often has limited treatment options.
• What they did: The study compared resistance pathways in KRASG12D and KRASG12R mutants using daraxonrasib, a RAS(ON) inhibitor, and identified allele-specific adaptive routes involving CypA downregulation or EGFR/RASWT activation.
• The result: Targeting the dominant resistance pathway in KRASG12R tumors with trametinib-based therapy led to significant clinical benefit, demonstrating that allele-specific network topology guides effective personalized treatment strategies.