PXD029432 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 | 2022-11-28 |
AnnouncementXML | Submission_2022-11-28_15:53:50.542.xml |
DigitalObjectIdentifier | https://dx.doi.org/10.6019/PXD029432 |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Supported dataset by repository |
PrimarySubmitter | JohnKoomen |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive |
Dataset History
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. |
Publication List
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; |
Keyword List
submitter keyword: Ovarian Cancer, Phosphoproteomics, PARP1, BRCA |
Contact List
UweRix |
contact affiliation | Moffitt Cancer Center Tampa, FL, USA |
contact email | uwe.rix@mffitt.org |
lab head | |
JohnKoomen |
contact affiliation | Moffitt Cancer Center |
contact email | john.koomen@moffitt.org |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD029432
- Label: PRIDE project
- Name: Integrative functional proteomics identifies PARP1 protein complex differences and PARP inhibitor-mediated DDR and AKT-mTOR signaling in ovarian carcinoma: Phosphoproteomics