PXD034644-1

PXD034644 is an original dataset announced via ProteomeXchange.

Title	N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer.
Description	Breast cancer is the second most common cancer type worldwide, representing 25% of all cancers in women. PIK3CA is one of the most frequently mutated genes in breast cancer and mutations result in constitutive activation of the PI3K/mTOR pathway. More than 30 inhibitors against PI3K/mTOR are being tested in clinical trials, however, resistance mechanisms evolve frequently resulting in disease progression. The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. For this purpose, we used a genome-wide PiggyBac transposon mediated mutagenesis screen in a PIK3CAH1047R mutated murine tumor model. One of the tumor suppressor genes discovered was neurofibromin 1 (NF1). Using shRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of NF1 in murine and human PIK3CAH1047R cell lines and a patient derived xenograft organoid model, we found that NF1 loss reduces sensitivity to PI3Kα inhibition. Additionally, we find that loss of NF1 correlates with enhanced glycolysis and lower levels of ROS. Unexpectedly, treatment with NAC sensitized NF1 KO cells to PI3K inhibition in vitro, and in vivo. Global phospho-proteomics indicated that the combination with NAC enhances the inhibitory effect of PI3K inhibition on mTOR signaling, which inhibits proliferation of NF1 KO tumor cells. This raises the interesting possibility to combine PI3K inhibition with NAC especially in NF1 loss tumors
HostingRepository	PRIDE
AnnounceDate	2024-10-07
AnnouncementXML	Submission_2024-10-07_11:06:25.039.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Katarzyna Buczak
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-19 04:58:32	ID requested
⏵ 1	2024-10-07 11:06:25	announced

Dataset with its publication pending

submitter keyword: TMT,PI3K alpha inhibition, phospho proteomics,Breast cancer

Alexander Schmidt
contact affiliation	Proteomics Core Facillity, Biozentrum, University of Basel 4056 Basel, Switzerland
contact email	alex.schmidt@unibas.ch
lab head
Katarzyna Buczak
contact affiliation	Biozentrum, University of Basel
contact email	katarzyna.buczak@unibas.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD034644
     1. Label: PRIDE project
     2. Name: N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer.