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

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Abstract

Radiotherapy (RT) is a central treatment for prostate cancer (PCa), relying on the induction of DNA double-strand breaks (DSBs). Tumor ability to repair these breaks limits RT efficacy, making DSB repair inhibitors potential radiosensitizers. However, many of these inhibitors lack tumor specificity and harm normal cells. 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+). In this study, we demonstrate that ERG+ tumors shift DSB repair toward the poly(ADP-ribose) polymerase 1–dependent end-joining (PARP1-EJ) pathway. Proteomic and Western blot analyses revealed elevated PARP1, XRCC1, and LIG3 levels in ERG+ cells. Notably, PARP inhibition with olaparib increased residual γH2AX/53BP1 foci postirradiation in ERG+ cells, indicating enhanced radiosensitization. In tissue slice cultures (TSCs) from 53 tumors of patients with high-risk PCa, olaparib selectively increased γH2AX/53BP1 foci selectively in ERG+ samples. ERG+ patient–derived organoids also showed significantly delayed growth when treated with olaparib plus RT, compared with 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 those in ERG+ cells. This was confirmed by medium exchange experiments. These findings suggest that ERG expression promotes dependency on the PARP1-EJ pathway, rendering ERG+ PCa more susceptible to PARP inhibition. This supports combining PARP inhibitors with RT for tumor-selective radiosensitization in ERG+ patients.

Authors

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