KRAS amplification fuels resistance to a RAS(ON) inhibitor in pancreatic cancer, guiding combo therapies

In pancreatic ductal adenocarcinoma, resistance to the RAS(ON) inhibitor daraxonrasib emerges in about 59% of patients, driven mainly by acquired KRAS amplification and alterations in RTK/MAPK/PI3K pathways, with no therapy‑emergent secondary KRAS mutations observed. Preclinical models validate these resistance mechanisms and show that combining daraxonrasib with RTK inhibitors, DDR-targeting agents, or the mutant KRAS G12D inhibitor zoldonrasib can prevent resistance, informing rational combination strategies for PDAC.