ERG inhibition selectively sensitizes ERG-positive prostate cancer to radiation through DNA repair vulnerabilities and enhances response to androgen receptor inhibitors.
14 affiliations
- 1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 2Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 3Section of Mass Spectrometric Proteomics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
- 4Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
- 5Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 6Department of Otorhinolaryngology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 7Department of Molecular & Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
- 8Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
- 9Department of Urology, Koc University Hospital, Istanbul, Türkiye.
- 10Department of Oncology, II Med. Klinik, Hematology, BMT With Section Pneumology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- 11Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [email protected].
- 12Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [email protected].
- 13Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [email protected].
- 14Department of Oncology, II Med. Klinik, Hematology, BMT With Section Pneumology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [email protected].
Abstract
Background
ERG overexpression, driven by TMPRSS2-ERG gene fusion, occurs in ~ 50% of prostate cancers (PCa) and defines a molecular subtype with distinct therapeutic vulnerabilities. Radiotherapy (RT) is a cornerstone for localized and locally advanced PCa, yet substantial number of patients experience treatment failure. This study investigates whether direct ERG inhibition selectively impairs the resolution of DNA damage signaling and radiosensitizes ERG-positive PCa, providing a precision medicine strategy.Methods
ERG-positive VCaP cells, ERG-negative DU145/BPH1 cells, ex vivo patient PCa tissue slice cultures (TSCs, n = 14 from 10 patients), and patient-derived organoids (PDOs, n = 2) were treated with ERG inhibitors (ERGi-USU, VPC-18005) or ERG siRNA ± irradiation (2-6 Gy). DNA double-strand break (DSB) repair was assessed via γ H2AX/53BP1 immunofluorescence and pEJ-GFP reporter assay. Clonogenic survival was evaluated in 2D/3D assays. Label-free quantitative LC-MS/MS proteomics identified differentially regulated pathways, validated by immunoblotting. Promoter activity was measured using GLuc-ON™ Promoter Reporter plasmids.Results
Here, we show that direct ERG inhibition selectively delays the resolution of radiation-induced DSB-associated damage signals and reduces end-joining activity in ERG-positive models, leading to enhanced radiosensitivity. In ERG-positive VCaP cells, ex vivo patient PCa tissue slices, and patient-derived PCa organoids, treatment with ERG inhibitors or ERG-targeted siRNA significantly increased residual γH2AX/53BP1 foci and reduced clonogenic survival following irradiation, whereas ERG-negative tumors remained unaffected. Quantitative LC-MS/MS proteomics, confirmed by immunoblotting and promoter activity assay, revealed that ERG inhibition downregulates key PARP1-mediated end-joining pathway components, including PARP1, LIG3, XRCC1, and the end-resection factor MRE11. Functional assays showed that ERG and PARP inhibition converge on a common mechanism to block alternative end joining, whereas combined ERG and androgen receptor (AR) pathway inhibition further suppressed growth in ERG-positive PCa spheroids and PDOs, probably through metabolic reprogramming.Conclusions
These data position ERG as a master regulator of DNA repair vulnerabilities in PCa and provide a strong mechanistic rationale for clinical evaluation of ERG-directed radiosensitization and combination therapy strategies in molecularly defined ERG-positive disease.
Related
- Glaucocalyxin A sensitizes ovarian cancer cells to PARP inhibitors by inducing DNA damage
- 1105 HER3 inhibition sensitizes metastatic colorectal and pancreatic cancer to immunotherapy
- Nicotinic acid starvation sensitizes nicotinate phosphoribosyltransferase-expressing tumors to nicotinamide phosphoribosyltransferase inhibition
- Fibrillarin Resists Cellular Senescence Via SIRT1‐Dependent Nicotinamide Metabolism and Its Inhibition Sensitizes Senolytic Therapy in Esophageal Squamous Cell Carcinoma
- Inhibition of the ATR-CHK1 signaling pathway sensitizes MCPyV-positive Merkel cell carcinoma to gemcitabine
BibTeX
@article{moustafa2026inhibition,
title = {{ERG inhibition selectively sensitizes ERG-positive prostate cancer to radiation through DNA repair vulnerabilities and enhances response to androgen receptor inhibitors.}},
author = {Ayham Moustafa and Mohamed E Elsesy and Bente Siebels and Jan Hahn and Su-Jung Oh-Hohenhorst and Carlotta Schudy and Thorsten Rieckmann and Susanne Burdak-Rothkamm and Derya Tilki and Tobias Maurer and Cordula Petersen and Kai Rothkamm and Gunhild von Amsberg and Carsten Bokemeyer and Hartmut Schlüter and Sabrina Köcher and Wael Y Mansour},
journal = {Journal of experimental \& clinical cancer research : CR},
year = {2026},
month = oct,
doi = {10.1186/s13046-026-03854-9},
url = {https://europepmc.org/article/MED/42926195},
note = {CC BY},
}
RIS
TY - JOUR
TI - ERG inhibition selectively sensitizes ERG-positive prostate cancer to radiation through DNA repair vulnerabilities and enhances response to androgen receptor inhibitors.
AU - Ayham Moustafa
AU - Mohamed E Elsesy
AU - Bente Siebels
AU - Jan Hahn
AU - Su-Jung Oh-Hohenhorst
AU - Carlotta Schudy
AU - Thorsten Rieckmann
AU - Susanne Burdak-Rothkamm
AU - Derya Tilki
AU - Tobias Maurer
AU - Cordula Petersen
AU - Kai Rothkamm
AU - Gunhild von Amsberg
AU - Carsten Bokemeyer
AU - Hartmut Schlüter
AU - Sabrina Köcher
AU - Wael Y Mansour
PY - 2026
DA - 2026/10/23
JO - Journal of experimental & clinical cancer research : CR
DO - 10.1186/s13046-026-03854-9
UR - https://europepmc.org/article/MED/42926195
AB - Background ERG overexpression, driven by TMPRSS2-ERG gene fusion, occurs in ~ 50% of prostate cancers (PCa) and defines a molecular subtype with distinct therapeutic vulnerabilities. Radiotherapy (RT) is a cornerstone for localized and locally advanced PCa, yet substantial number of patients experience treatment failure. This study investigates whether direct ERG inhibition selectively impairs the resolution of DNA damage signaling and radiosensitizes ERG-positive PCa, providing a precision medicine strategy.Methods ERG-positive VCaP cells, ERG-negative DU145/BPH1 cells, ex vivo patient PCa tissue slice cultures (TSCs, n = 14 from 10 patients), and patient-derived organoids (PDOs, n = 2) were treated with ERG inhibitors (ERGi-USU, VPC-18005) or ERG siRNA ± irradiation (2-6 Gy). DNA double-strand break (DSB) repair was assessed via γ H2AX/53BP1 immunofluorescence and pEJ-GFP reporter assay. Clonogenic survival was evaluated in 2D/3D assays. Label-free quantitative LC-MS/MS proteomics identified differentially regulated pathways, validated by immunoblotting. Promoter activity was measured using GLuc-ON™ Promoter Reporter plasmids.Results Here, we show that direct ERG inhibition selectively delays the resolution of radiation-induced DSB-associated damage signals and reduces end-joining activity in ERG-positive models, leading to enhanced radiosensitivity. In ERG-positive VCaP cells, ex vivo patient PCa tissue slices, and patient-derived PCa organoids, treatment with ERG inhibitors or ERG-targeted siRNA significantly increased residual γH2AX/53BP1 foci and reduced clonogenic survival following irradiation, whereas ERG-negative tumors remained unaffected. Quantitative LC-MS/MS proteomics, confirmed by immunoblotting and promoter activity assay, revealed that ERG inhibition downregulates key PARP1-mediated end-joining pathway components, including PARP1, LIG3, XRCC1, and the end-resection factor MRE11. Functional assays showed that ERG and PARP inhibition converge on a common mechanism to block alternative end joining, whereas combined ERG and androgen receptor (AR) pathway inhibition further suppressed growth in ERG-positive PCa spheroids and PDOs, probably through metabolic reprogramming.Conclusions These data position ERG as a master regulator of DNA repair vulnerabilities in PCa and provide a strong mechanistic rationale for clinical evaluation of ERG-directed radiosensitization and combination therapy strategies in molecularly defined ERG-positive disease.
SN - 0392-9078
SN - 1756-9966
ER -