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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The TMPRSS2:ERG gene fusion is a key driver in many prostate cancers, but its precise role in cancer progression and treatment sensitivity is not fully understood.
• Understanding the molecular mechanisms by which ERG influences cancer cell biology is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the functional consequences of ERG overexpression on DNA repair pathways in prostate cancer.
• To determine if ERG-driven alterations in DNA repair create vulnerabilities that can be exploited therapeutically, particularly in combination with radiotherapy.

Main Methods:

• Utilized human prostate cancer cell lines with ERG overexpression.
• Analyzed DNA double-strand break repair pathway utilization using molecular assays.
• Investigated the impact of poly(ADP-ribose) polymerase 1 (PARP1) inhibition and radiotherapy on tumor cell viability.
• Validated findings in patient-derived prostate cancer organoids.

Main Results:

• ERG overexpression rewires DNA double-strand break repair towards a PARP1-dependent alternative end-joining pathway without impairing canonical repair.
• This rewiring creates a dependency on PARP1 in ERG-positive prostate cancer cells.
• Radiotherapy exposure unmasks this PARP1 dependency, leading to selective sensitivity to PARP inhibition-mediated radiosensitization.
• Combined PARP1 inhibition and irradiation demonstrated tumor-selective cytotoxic effects in prostate cancer organoids.

Conclusions:

• ERG acts as a predictive biomarker for precision radiotherapy in prostate cancer.
• Targeting PARP1 in combination with radiotherapy represents a tumor-selective strategy to enhance treatment efficacy in ERG-positive prostate cancers.