PXD060964-1

PXD060964 is an original dataset announced via ProteomeXchange.

Title	ERG overexpression is a predictive biomarker for PARP-inhibitor-mediated selective radiosensitization in prostate cancer – a proof of concept study
Description	Radiotherapy (RT) is a key treatment for prostate cancer (PCa), relying on the ability to induce DNA damage, particularly double-strand breaks (DSBs). The success of RT depends on tumor radiosensitivity and the ability to repair DSBs, making inhibitors of DSB repair enzymes a potential strategy for radiosensitization. However, these inhibitors often lack tumor specificity and can be toxic to normal cells. Thus, tumor-specific radiosensitization strategies are needed for PCa. PCa is frequently associated with chromosomal rearrangements, including the TMPRSS2-ERG translocation, which leads to ERG overexpression (ERG+), present in ~50% of PCa patients. In this study, we show that ERG+ expression shifts DSB repair to the PARP1-dependent end joining (PARP1-EJ) pathway. Western blotting revealed increased expression of PARP1, XRCC1, and LIG3 in ERG+ cells. Notably, PARP inhibition with olaparib increased residual H2AX/53BP1 foci in ERG+ cells after ionizing radiation (IR), rendering cellular radiosensitization by PARPi. Using ex vivo tissue slice (TSC) cultures from 53 tumor tissues of 40 high-risk PCa patients. … Olaparib treatment significantly increased H2AX/53BP1 foci selectively in ERG+ samples, suggesting that ERG expression predicts sensitivity to PARPi as radiosensitizers. Additionally, ERG+ patient-derived organoids showed a significant growth delay when treated with olaparib plus IR, compared to either treatment alone. Interestingly, the radiosensitizing effect of olaparib was also observed in ERG-negative cells within the TSC of ERG+ patients, with residual 53BP1 foci levels comparable to those in ERG+ cells. This was confirmed by medium exchange experiments. In conclusion, ERG overexpression drives a shift in DSB repair to the PARP1-EJ pathway, enhancing radiosensitivity to PARP inhibition. These findings support combining PARP inhibitors with RT for tumor-specific radiosensitization in ERG+ PCa patients.
HostingRepository	PRIDE
AnnounceDate	2026-01-08
AnnouncementXML	Submission_2026-01-08_09:09:56.139.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bente Siebels
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-19 07:13:42	ID requested
⏵ 1	2026-01-08 09:09:56	announced

Dataset with its publication pending

submitter keyword: Prostate cancer, ERG overexpression, PARP inhibition, DNA double-strand break repair,Radiotherapy

Prof. Hartmut Schlüter
contact affiliation	Center for Diagnostics, Section Mass Spectrometry and Protemics, University Medical Center Hamburg-Eppednorf, Hamburg, Germany
contact email	hschluet@uke.de
lab head
Bente Siebels
contact affiliation	Section for Mass spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf
contact email	b.siebels@uke.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060964
     1. Label: PRIDE project
     2. Name: ERG overexpression is a predictive biomarker for PARP-inhibitor-mediated selective radiosensitization in prostate cancer – a proof of concept study