PXD065233-1

PXD065233 is an original dataset announced via ProteomeXchange.

Title	Phosphoinositide 3-kinase regulates basal wild-type RAS signaling to confer resistance to KRAS inhibition
Description	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 show here that phosphoinositide 3-kinase (PI3K) plays a major role in this resistance through upstream activation of wild-type RAS signaling – beyond its known KRAS effector function. Combining proximity labeling, CRISPR screens, live-cell imaging, and functional assays we found 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. We further demonstrate that inhibiting PI3K enhances sensitivity to mutant-specific KRAS inhibitors in PDAC cells, including cells with clinically identified PIK3CA mutations. Our findings refine RAS-PI3K signaling paradigms, reveal that PI3K-driven wild-type RAS activation drives resistance to KRAS inhibition, and illuminate new avenues for augmenting KRAS-targeted therapies in PDAC.
HostingRepository	PRIDE
AnnounceDate	2026-04-28
AnnouncementXML	Submission_2026-04-27_18:40:09.866.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Wenxue Li
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-19 15:22:26	ID requested
⏵ 1	2026-04-27 18:40:10	announced

Dataset with its publication pending

submitter keyword: Phosphoinositide 3-kinase, proteomics, RAS signaling, KRAS

Yansheng Liu
contact affiliation	Yale School of Medicine
contact email	yansheng.liu@yale.edu
lab head
Wenxue Li
contact affiliation	Yale University
contact email	wenxue.li@yale.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD065233
     1. Label: PRIDE project
     2. Name: Phosphoinositide 3-kinase regulates basal wild-type RAS signaling to confer resistance to KRAS inhibition