Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.

Over 59% of pancreatic cancer patients treated with daraxonrasib develop resistance through RAS pathway alterations, including KRAS amplification and RTK upregulation.

• Why it matters: Understanding resistance mechanisms is crucial to improve targeted therapies for pancreatic ductal adenocarcinoma, which often exhibits poor responses to current treatments.
• What they did: Targeted sequencing of circulating tumor DNA from 44 patients revealed resistance-associated genomic changes, and preclinical models confirmed these mechanisms, guiding combination therapy strategies.
• The result: Combining daraxonrasib with agents targeting DNA damage, RTKs, or mutant RAS(ON) inhibitors prevented resistance in models, paving the way for improved therapeutic approaches in PDAC.