ERG overexpression is a predictive biomarker for PARP-inhibitor-mediated selective radiosensitization in prostate cancer – a proof of concept study

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.