TMPRSS2:ERG-directed radiosensitization: exploiting DNA repair rewiring in gene fusion-positive prostate cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41837288.
- Also identified by DOI 10.1172/JCI203657 and PMC identifier 12987609.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Prostatic Neoplasms
- Oncogene Proteins, Fusion
- DNA Repair
- Radiation Tolerance