PXD029432

PXD029432 is an original dataset announced via ProteomeXchange.

Title	Integrative functional proteomics identifies PARP1 protein complex differences and PARP inhibitor-mediated DDR and AKT-mTOR signaling in ovarian carcinoma: Phosphoproteomics
Description	BRCA1/2-deficient ovarian carcinoma (OC) has been shown to be particularly sensitive to PARP inhibitors (PARPis) and BRCA1/2 mutation status is currently used as a predictive biomarker for PARPi therapy. Despite eliciting major clinical benefit for the majority of patients, a significant proportion of BRCA1/2-deficient OC tumors do not respond to PARPis for reasons that are incompletely understood. Using an integrated chemical, phospho- and ADP-ribosylation proteomics approach we sought to develop additional mechanism-based biomarker candidates for PARPi therapy in OC and identify new targets for combination therapy to overcome primary resistance. Chemical proteomics with PARPi baits in a BRCA1-isogenic OC cell line pair, as well as patient-derived BRCA1-profiecient and deficient tumor samples, and subsequent validation by co-immunoprecipitation showed differential PARP1 and PARP2 protein complex composition with Ku70 and Ku80 in PARPi-sensitive, BRCA1-deficient UWB1.289 (UWB) cells compared to PARPi-insensitive, BRCA1-reconstituted UWB1.289 (UWB+B) cells. Global phosphoproteomics and ADP-ribosylation proteomics furthermore revealed that rucaparib induced the cell cycle pathway and NHEJ pathway in UWB cells, but down-regulated ErbB signaling in UWB+B cells. In addition, we observed AKT PARylation and pro-survival AKT-mTOR signaling in UWB+B cells after PARPi treatment. Consistently, synergy of PARPis with DNAPK or AKT inhibitors was more pronounced in UWB+B cells identifying these pathways as actionable vulnerabilities. In conclusion, the combination of chemical proteomics, phosphoproteomics and ADP-ribosylation proteomics can identify differential PARP1/2 complexes and diverse, but actionable drug compensatory signaling in OC.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:18:32.458.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD029432
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-10-29 04:26:37	ID requested
1	2022-11-28 15:53:51	announced
⏵ 2	2023-11-14 07:18:34	announced	2023-11-14: Updated project metadata.

Deng O, Dash S, Nepomuceno TC, Fang B, Yun SY, Welsh EA, Lawrence HR, Marchion D, Koomen JM, Monteiro AN, Rix U, Integrated proteomics identifies PARP inhibitor-induced prosurvival signaling changes as potential vulnerabilities in ovarian cancer. J Biol Chem, 298(11):102550(2022) [pubmed]

10.6019/PXD029432;

submitter keyword: Ovarian Cancer, Phosphoproteomics, PARP1, BRCA

Uwe Rix
contact affiliation	Moffitt Cancer Center Tampa, FL, USA
contact email	uwe.rix@mffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029432
     1. Label: PRIDE project
     2. Name: Integrative functional proteomics identifies PARP1 protein complex differences and PARP inhibitor-mediated DDR and AKT-mTOR signaling in ovarian carcinoma: Phosphoproteomics