PXD033530

PXD033530 is an original dataset announced via ProteomeXchange.

Title	PARP1-SNAI2 Transcription Axis Drives Resistance to PARP Inhibitor, Talazoparib
Description	The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.
HostingRepository	PRIDE
AnnounceDate	2022-07-08
AnnouncementXML	Submission_2022-07-08_01:54:53.615.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD033530
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Xia Ding
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	2022-04-28 01:38:01	ID requested
⏵ 1	2022-07-08 01:54:54	announced

Dataset with its publication pending

submitter keyword: PARP1, Talazoparib, drug resistance

Todd VanArsdale
contact affiliation	Tumor biology, Oncology Research Unit, Pfizer
contact email	todd.vanarsdale@pfizer.com
lab head
Xia Ding
contact affiliation	Pfizer, Inc.
contact email	xia.ding2@pfizer.com
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/2022/07/PXD033530

PRIDE project URI

• PRIDE
  1. PXD033530
     1. Label: PRIDE project
     2. Name: PARP1-SNAI2 Transcription Axis Drives Resistance to PARP Inhibitor, Talazoparib