PXD020484

PXD020484 is an original dataset announced via ProteomeXchange.

Title	The non-canonical PARP1 inhibitor target, PARP16, contributes to talazoparib polypharmacology and synergy with WEE1 inhibitors: Phosphoproteomics
Description	PARP1 inhibitors (PARP1is ) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determined the differential efficacy of multiple clinical PARP1is in SCLC cells. Compared to the other PARP1is (rucaparib, olaparib and niraparib), talazoparib displayed the highest potency across SCLC, also in SLFN11-negative cells. Chemical proteomics identified PARP16 as a unique talazoparib target in addition to PARP1. Silencing PARP16 significantly reduced cell survival, particularly in combination with PARP1 inhibition. Drug combination screening revealed talazoparib synergy with the WEE1/PLK1 inhibitor, adavosertib. Global phosphoproteomics identified disparate effects on cell cycle and DNA damage response signaling, illustrating underlying mechanisms. Synergy with adavosertib was more pronounced for talazoparib than olaparib and silencing PARP16 further reduced cell survival in combination with olaparib and adavosertib. Together, these data suggest that PARP16 contributes to talazoparib’s overall mechanism of action and constitutes a new actionable target in SCLC.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:24:10.854.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD020484
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	2020-07-21 21:47:27	ID requested
1	2021-07-21 07:03:32	announced
⏵ 2	2024-10-22 05:24:11	announced	2024-10-22: Updated project metadata.

10.6019/PXD020484;

submitter keyword: Adavosertib, Phosphoproteomics, PARP16, Lung cancer, PARP1, Polypharmacology,PARP inhibitor, Ewing’s sarcoma, Off-target, Talazoparib

Uwe Rix, PhD
contact affiliation	Moffitt Cancer Center Tampa, FL, USA
contact email	uwe.rix@moffitt.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. PXD020484
     1. Label: PRIDE project
     2. Name: The non-canonical PARP1 inhibitor target, PARP16, contributes to talazoparib polypharmacology and synergy with WEE1 inhibitors: Phosphoproteomics