TMPRSS2:ERG–directed radiosensitization: exploiting DNA repair rewiring in gene fusion–positive prostate cancer
Xiaoju Wang, Arul M. Chinnaiyan
Xiaoju Wang, Arul M. Chinnaiyan
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Commentary

TMPRSS2:ERG–directed radiosensitization: exploiting DNA repair rewiring in gene fusion–positive prostate cancer

Abstract

The TMPRSS2:ERG gene fusion is a truncal oncogenic event in a large subset of prostate cancers, yet its clinical relevance has remained unclear. In this issue of the JCI, Köcher et al. have demonstrated that ERG overexpression in human prostate cancer cells rewired DNA double-strand break repair toward a poly(ADP-ribose) polymerase 1–dependent (PARP1-dependent) alternative end-joining pathway without disrupting canonical repair. This repair bias created a conditional dependency on PARP1 that was exposed by radiotherapy, rendering ERG-positive tumors selectively sensitive to PARP inhibition–mediated radiosensitization. The tumor-selective cytotoxic effect of combined PARP1 inhibition and irradiation was corroborated in human-derived prostate cancer organoids. These findings establish ERG as a predictive biomarker for precision radiotherapy and highlight a tumor-selective strategy to enhance radiotherapeutic efficacy in prostate cancer.

Authors

Xiaoju Wang, Arul M. Chinnaiyan

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Figure 1

ERG-driven DNA repair rewiring creates a therapeutic window for radiosensitization.

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ERG-driven DNA repair rewiring creates a therapeutic window for radiosen...
Köcher et al. (8) showed that the TMPRSS2:ERG fusion reprograms DNA double-strand break (DSB) repair in prostate cancer to create a selective vulnerability to PARP inhibitor–mediated radiosensitization. (A) In ERG-negative cells, radiation-induced DSBs are predominantly repaired by canonical nonhomologous end-joining (NHEJ) and homologous recombination (HR), and PARP inhibition (PARPi) has minimal impact. (B) In contrast, ERG overexpression shifts DSB repair toward PARP1-dependent alternative end-joining (Alt-EJ) without impairing HR or NHEJ. Upon PARPi during radiotherapy, ERG-positive cells lose their dominant repair pathway, resulting in persistent γH2AX/53BP1 foci, genomic instability, and enhanced tumor cell death. (C) Thus, ERG expression serves as a predictive biomarker for tumor-selective radiosensitization.