GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE315nnn/GSE315796/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE315796GEOGSEfalseSingle-cell RNAseq of from murine pancreas tumor (FPC)Oncogenic KRAS drives pancreatic ductal adenocarcinoma (PDAC), yet resistance to RAS antagonists limits benefit. We deployed two complementary preclinical PDAC models, including a degron-regulated KRASG12D-dependent transplantation model, and a KrasG12V-driven PDAC mouse model treated with the RAS(ON) multi-selective inhibitor, RMC-7977, to describe therapeutic response and resistance mechanisms. KRASG12D degradation provoked RAS-dependent relapse, characterized by compensatory wild-type (WT) RAS upregulation, restored MAPK signaling and proliferation, and a shift towards hybrid cancer cell states. RMC-7977 treatment triggered rapid RAS-independent resistance within 7 days, distinguished by suppressed MAPK yet restored proliferation with increased epithelial differentiation, and upregulation of Fyn. Antagonists of WT RAS or FYN attenuated resistance; and combining FYN antagonism with RMC-7977 prevented the uncoupling of MAPK signaling from cell proliferation in the respective KrasG12V PDAC model. Our findings identify distinct adaptive pathways orchestrating RAS-dependent versus RAS-independent resistance in PDAC and propose combination strategies for clinical evaluation to enhance KRAS-directed therapy durability.2026/09/07GSE315796GSM9437630GSM9437631GSM9437632GSM9437633GSM9437627GSM9437628GSM943762930172315796Mus musculus