Advertisement

ResearchIn-Press PreviewClinical ResearchOncology Open Access | 10.1172/JCI194949

Overexpression of the ERG oncogene in prostate cancer identifies candidates for PARP inhibitor-based radiosensitization

Sabrina Köcher,1 Mohamed E. Elsesy,1 Ayham Moustafa,1 Wahid Mohammadi,1 Adriana Perugachi Heinsohn,1 Yamini Nagaraj,2 Su Jung Oh-Hohenhorst,2 Jan Hahn,3 Bente Siebels,4 Thomas Mair,4 Susanne Burdak-Rothkamm,1 Pierre Tennstedt,2 Ronald Simon,5 Tobias Lange,6 Derya Tilki,2 Thorsten Frenzel,1 Tobias Maurer,2 Cordula Petersen,1 Hartmut Schlüter,4 Carsten Bokemeyer,7 Gunhild von Amsberg,2 Kai Rothkamm,1 and Wael Y. Mansour1

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Köcher, S. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Elsesy, M. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Moustafa, A. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Mohammadi, W. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Perugachi Heinsohn, A. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Nagaraj, Y. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Oh-Hohenhorst, S. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Hahn, J. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Siebels, B. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Mair, T. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Burdak-Rothkamm, S. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Tennstedt, P. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Simon, R. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Lange, T. in: PubMed | Google Scholar |

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Tilki, D. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Frenzel, T. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Maurer, T. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Petersen, C. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Schlüter, H. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Bokemeyer, C. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by von Amsberg, G. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Rothkamm, K. in: PubMed | Google Scholar

1Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Section of Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

6Anatomy Institute, Luebeck University, Luebeck, Germany

7Dept of Oncology, Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Find articles by Mansour, W. in: PubMed | Google Scholar

Published February 3, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI194949.
Copyright © 2026, Köcher et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 3, 2026 - Version history
View PDF
Abstract

Radiotherapy (RT) is a central treatment for prostate cancer (PCa), acting by inducing DNA double-strand breaks (DSBs). Tumor ability to repair these breaks limits RT efficacy, making DSB repair inhibitors potential radiosensitizers. Therefore, tumor-specific radiosensitization strategies are critically needed for PCa. Approximately 50% of PCa cases harbor the TMPRSS2-ERG gene fusion, leading to overexpression of the ERG transcription factor (ERG+). We demonstrate that ERG+ tumors shift DSB repair toward the PARP1-dependent end-joining (PARP1-EJ) pathway. Proteomic and western blot analyses revealed elevated PARP1, XRCC1, and LIG3 in ERG+ cells. PARP inhibition with olaparib increased residual γH2AX/53BP1 foci post-irradiation in ERG+ cells, indicating enhanced radiosensitization. In tissue-slice-cultures (TSCs) from 53 tumors of 40 high-risk PCa patients, olaparib selectively increased H2AX/53BP1 foci selectively in ERG+ samples. ERG+ patient-derived organoids also showed significantly delayed growth and survival when treated with olaparib plus RT compared to either treatment alone. Interestingly, ERG-negative cells within ERG+ TSCs were similarly radiosensitized by olaparib, likely through bystander effect, with residual 53BP1 foci levels comparable to ERG+ cells, confirmed by medium exchange experiments. These findings suggest that ERG expression promotes dependency on PARP1-EJ, rendering ERG+ PCa more susceptible to PARP inhibition. Combining PARP inhibitors with RT may offer a tumor-selective radiosensitization for ERG+ PCa patients.

Graphical Abstract
graphical abstract
Supplemental material

View

View Supplementary Table 1_all identified proteins+labels description

View Supplementary Table 2_ ANOVA_Unchanged proteins cross cell lines

View Supplementary Table 3_ ANOVA_FDR

View Supplementary Table 4 Characteristics of included prostate cancer patients subjected to radical prostatectomy.

View SupplementaryTable 5_ERG Scores and PiER index

View Supplementary Table 6 AR and ERG status in TSCs from PCa patients

View Unedited blot and gel images

Version history
  • Version 1 (February 3, 2026): In-Press Preview
Advertisement
Advertisement