ArticleCancer research2026
PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition.
Article in Cancer research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
1 citing paper in PubMed.
- Application of Systems Genetics to Investigate Molecular Pathology of Early-Onset Colorectal Cancer.Chemical biology & drug design · 2026Review
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9 authors.
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Abstract
Despite 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 phosphoinositide 3-kinase (PI3K) plays a major role in this resistance through upstream activation of wild-type (WT) 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 mitogen-activated protein kinase (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 WT RAS activation drives resistance to KRAS inhibition, and illuminate avenues for augmenting KRAS-targeted therapies in PDAC. SIGNIFICANCE: PI3K plays a functional upstream role in assembling wild-type RAS signaling complexes that confer KRAS inhibitor resistance, providing a rationale for combined targeting of PI3K and KRAS in pancreatic cancer.
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