GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE335nnn/GSE335219/suppl/filelist.txtftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE335nnn/GSE335219/suppl/GSE335219_RAW.tarftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE335nnn/GSE335219/primaryOK200OtherHomo sapiensOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE335219GEOGSEfalseAcquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancerDaraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a Phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized Phase 3 RASolute 302 clinical trial . Here, we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pre- and end of treatment ctDNA samples from 44 patients in the Phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26/44; 59%) of these patients including, most notably, mutant KRAS amplifications in one third (16/44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4/44, 9%), MAPK (11/44, 25%) and PI3K (4/44, 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found or mechanistically established concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification, and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA Damage Response (DDR), receptor tyrosine kinases (RTKs), or with the mutant-selective RAS(ON) G12D inhibitor zoldonrasib, averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.2026/06/16GSE335219GSM9808344GSM980834534284335219Homo sapiens