PXD017826-2

PXD017826 is an original dataset announced via ProteomeXchange.

Title	PBRM1 deficiency is synthetic lethal with PARP inhibitors in human cancers
Description	Polybromo-1 (PBRM1), which encodes a specific subunit of the pBAF chromatin remodeling complex, is inactivated in multiple malignancies including 50% of clear cell renal cell carcinoma. At present, a therapeutic strategy that selectively targets PBRM1 defects does not exist. PBRM1 is involved in multiple cellular processes including transcription, replication and DNA repair. Using high-throughput screens and multiple isogenic and non-isogenic models, we found that PBRM1 defects cause synthetic lethality with several clinical PARP inhibitors, both in vitro and in vivo. This effect was enhanced using combinations with either small molecule ATR or BET inhibitors. Mechanistically, PBRM1 defects caused increased replication stress, R-loop formation and genomic instability that was exacerbated by PARP inhibitors. We also found that PARP and ATR inhibitors activate the cGAS-STING innate immunity pathway in PBRM1-deficient but not in PBRM1-proficient cells. These data provide the pre-clinical rationale for assessing PARP inhibitors as a monotherapy or in combination with ATR inhibitors or immune checkpoint inhibitors, in patients with PBRM1-deficient cancers.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:32:56.962.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	James Wright
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-03-02 05:12:03	ID requested
1	2022-02-21 06:44:38	announced
⏵ 2	2024-10-22 05:32:57	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: TMT, msms, PARP inhibitors,Cancer

Jyoti Choudhary
contact affiliation	The Institute of Cancer research
contact email	jyoti.choudhary@icr.ac.uk
lab head
James Wright
contact affiliation	The Institute of Cancer Research
contact email	james.wright@icr.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017826
     1. Label: PRIDE project
     2. Name: PBRM1 deficiency is synthetic lethal with PARP inhibitors in human cancers