PXD065233

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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/04/PXD065233

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