PXD067648-1

PXD067648 is an original dataset announced via ProteomeXchange.

Title	Distinct (Phospho)proteomic Landscapes of PIK3CA Mutants Reveal Insulin-Mediated Reactivation of PI3K Pathway and Adaptive MAPK Signaling
Description	Oncogenic mutations in p110α subunit of phosphatidylinositol-3-kinase (PI3K), primarily H1047R in the kinase domain and E545K in the helical domain, induce constitutive PI3K/AKT pathway activation, driving tumor progression. Isoform-specific inhibitors such as alpelisib have been developed, but their clinical efficacy is often compromised by on-target metabolic side effects, particularly hyperglycemia and insulin feedback that reactivates PI3K signaling. To better understand the signaling response in PI3K mutants and insulin-mediated tumor resistance, using MCF10A epithelial cells harboring PI3K hotspot mutations (H1047R or E545K), we conducted comprehensive proteomic and phosphoproteomic analyses under varying conditions—alpelisib treatment, insulin stimulation, and their combination. We observed mutation specific responses in growth kinetics, proteome states, and dynamic signaling response. We observed that insulin effectively rescues mutant cells from alpelisib-induced inhibition through the reactivation of PI3K pathway and the adaptive reprogramming, especially activation of the MAPK pathways. These findings indicate that combination therapies targeting both the PIK3CA mutation and MAPK pathways may be necessary to overcome challenges faced by PI3Kα inhibitors and achieve more durable clinical responses.
HostingRepository	PRIDE
AnnounceDate	2026-09-07
AnnouncementXML	Submission_2026-09-07_04:29:24.599.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Fujia Wang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-23 11:12:33	ID requested
⏵ 1	2026-09-07 04:29:25	announced

Wang F, Altelaar M, Stecker KE, Mutant Breast Epithelial Cells. J Proteome Res, 25(7):3276-3289(2026) [pubmed]

10.1021/acs.jproteome.5c00907;

submitter keyword: proteomics

phosphoproteomics

PIK3CA mutation

Kelly E. Stecker
contact affiliation	Biomolecular Mass Spectrometry and Proteomics, Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands
contact email	k.e.stecker@uu.nl
lab head
Fujia Wang
contact affiliation	Utrecht University
contact email	f.wang3@uu.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067648
     1. Label: PRIDE project
     2. Name: Distinct (Phospho)proteomic Landscapes of PIK3CA Mutants Reveal Insulin-Mediated Reactivation of PI3K Pathway and Adaptive MAPK Signaling