PXD040422

PXD040422 is an original dataset announced via ProteomeXchange.

Title	PPP2R1A mutations cause ATR inhibitor synthetic lethality in ARID1A deficient ovarian clear cell carcinoma
Description	Ovarian clear cell carcinoma (OCCC) is a cancer of unmet need characterized by ARID1A mutation. Prior work identified an ARID1A/ATR synthetic lethality, information that led to phase II clinical trials. Using genome-wide CRISPR-Cas9 mutagenesis and interference screens, we identified protein phosphatase 2A (PP2A) subunits, including PPP2R1A, as determinants of ATRi sensitivity in ARID1A mutant OCCC. Analysis of an OCCCs cohort indicated that >1/3 possessed both PPP2R1A and ARID1A loss-of-function mutations. CRISPR-prime editing demonstrated that oncogenic PPP2R1A p.R183 missense mutations enhance in vitro and in vivo ATRi sensitivity in ARID1A mutant OCCC. OCCC patients with both ARID1A and PPP2R1A mutations also showed clinical responses to ATRi in a phase II trial. Mechanistically, this synthetic lethal effect is dependent upon WNK1 kinase, which opposes PP2A function. This data suggests that co-occurrence of PPP2R1A and ARID1A mutations in OCCC should be assessed as a biomarker of ATRi response in on-going clinical trials.
HostingRepository	PRIDE
AnnounceDate	2023-05-10
AnnouncementXML	Submission_2023-05-10_02:57:11.784.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	GraemeBenstead-Hume
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-27 05:17:56	ID requested
⏵ 1	2023-05-10 02:57:12	announced

Dataset with its publication pending

submitter keyword: ATR, ARID1A,Ovarian clear cell carcinoma, synthetic lethality

JyotiChoudhary
contact affiliation	Functional Proteomics Institute of Cancer Research
contact email	jyoti.choudhary@icr.ac.uk
lab head
GraemeBenstead-Hume
contact affiliation	ICR
contact email	ghume@icr.ac.uk
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/2023/05/PXD040422

PRIDE project URI

• PRIDE
  1. PXD040422
     1. Label: PRIDE project
     2. Name: PPP2R1A mutations cause ATR inhibitor synthetic lethality in ARID1A deficient ovarian clear cell carcinoma