# PARP inhibitors elicit distinct transcriptional programs in homologous recombination competent castration‐resistant prostate cancer

## TL;DR

This study shows that PARP1 activity and response to PARP inhibitors differ between African American and European American prostate cancer patients, and that different inhibitors cause unique gene expression changes.

## Contribution

The study reveals racial differences in PARP1 expression and distinct transcriptional effects of various PARP inhibitors in prostate cancer.

## Key findings

- African American and European American prostate cancer tissues show differences in PARP1 expression and activity.
- Different PARP inhibitors induce unique and overlapping transcriptional responses, including p53 pathway upregulation.
- These findings suggest potential for personalized PARP inhibitor treatment strategies.

## Abstract

Prostate cancer (PCa) is the second most lethal cancer in men in the US. African American (AA) men have twice the incidence and death rate of European American (EA) men. Advanced PCa shows increased expression and activity of the DNA damage/repair pathway enzyme, poly (ADP‐ribose) polymerase 1 (PARP1). PARP1 inhibitors (PARPi) are FDA‐approved for advanced PCa tumors with mutations in the homologous recombination repair (HRR) pathway. However, PARPi can provide benefit in model systems without HRR deficiencies. PARPi have distinct biochemical mechanisms, potencies, and toxicity profiles. While there is emerging evidence of differences in DNA damage/repair pathway enzyme expression between EA and AA men, PARP1 expression has not been fully explored in the context of race. This study hypothesized: (a) AA and EA PCa may respond differently to PARPi and (b) different PARPi may uniquely impact the transcriptome, irrespective of HRR status. Study results indicate a link between racial background and PARP1 expression/activity and define unique and overlapping transcriptional responses downstream of all five PARPi. These findings may lead to refined personalized recommendations for use of specific PARPi.

PARP inhibitors are used to treat a small subset of prostate cancer patients. These studies reveal that PARP1 activity and expression are different between European American and African American prostate cancer tissue samples. Additionally, different PARP inhibitors cause unique and overlapping transcriptional changes, notably, p53 pathway upregulation. These studies can ultimately lead to advances in personalized PARP inhibitor treatment options.