GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328107/primaryOK200OtherHomo sapiensOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328107GEOGSEfalsePI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS InhibitionDespite the availability of RAS inhibitors and the dependence of >90% of pancreatic ductal adenocarcinomas (PDAC) on oncogenic KRAS mutations, resistance to KRAS inhibition remains a serious obstacle. We showed here that PI3K plays a major role in this resistance through upstream activation of wild-type RAS signaling – beyond its known KRAS effector function. The combination of proximity labeling, CRISPR screening, live-cell imaging, and functional assays revealed that PI3K orchestrates phosphoinositide-mediated GAB1 recruitment to the plasma membrane, nucleating assembly of RAS signaling complexes that activate MAPK in an EGFR/SHP2/SOS1-dependent manner. Inhibiting PI3K enhanced sensitivity to mutant-specific KRAS inhibitors in PDAC cells, including in cells with clinically identified PIK3CA mutations. These findings refine RAS-PI3K signaling paradigms, reveal that PI3K-driven wild-type RAS activation drives resistance to KRAS inhibition, and illuminate avenues for augmenting KRAS-targeted therapies in PDAC.2026/04/28GSE328107GSM9672491GSM9672492GSM9672493GSM9672494GSM9672495GSM9672496GSM967249718573328107Homo sapiens