PXD059301-1

PXD059301 is an original dataset announced via ProteomeXchange.

Title	Targeting the ATM-TRMT10A-BRCA1 Axis Confers Synthetic Lethality to PARP Inhibition in Metastatic Castration-Resistant Prostate Cancer
Description	Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease characterized by its aggressive nature and resistance to anti-androgen therapies. Although PARP inhibitors (PARPis) have brought new hope for mCRPC patients with homologous recombination (HR) deficient, such as those lacking BRCA1/2, the utility of PARPi monotherapy is significantly restricted, with only 10%-15% of mCRPC patients with BRCA1/2 deficiencies achieving clinical benefit. Thus, there is a critical need for innovative therapeutic strategies for mCRPC patients without BRCA deficiency. In our current study, we elucidate the pivotal role of the ATM-TRMT10A-BRCA1 axis in mediating HR repair and PARPi resistance in mCRPC. We demonstrate that TRMT10A is phosphorylated at S28 by ATM after DNA damage. This phosphorylation is essential for the recruitment of BRCA1 to sites of DNA damage, thereby facilitating HR repair. Deletion of TRMT10A compromises HR repair, rendering tumor cells more sensitive to PARPi. Importantly, we show that TRMT10A expression is upregulated in mCRPC and is modulated by Ubiquitin Specific Peptidase 10 (USP10). Inhibition of USP10 with small molecular inhibitor Spautin-1 leads to TRMT10A degradation and enhances the sensitivity of tumors to PARPi in both cell-derived xenografts (CDX) and patient-derived xenografts (PDX). Our findings underscore the vital role of ATM-TRMT10A-BRCA1 axis in the vulnerability to PARP inhibitors and introduce a promising strategy perspective for exploring synthetic lethality. This approach, which involves the combination of PARP and USP10 inhibitors, could extend therapeutic benefits to a broader group of mCRPC patients without BRCA mutation.
HostingRepository	iProX
AnnounceDate	2024-12-30
AnnouncementXML	Submission_2024-12-29_19:36:05.533.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Min Deng
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-29 19:35:33	ID requested
⏵ 1	2024-12-29 19:36:05	announced

Dataset with its publication pending

submitter keyword: TRMT10A, BRCA1, PARPis, Prostate Cancer, Synthetic Lethality

Min Deng
contact affiliation	State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
contact email	dengmin@cicams.ac.cn
lab head
Min Deng
contact affiliation	State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
contact email	dengmin@cicams.ac.cn
dataset submitter

iProX dataset URI