Parp Inhibitor Response Is Enhanced in Prostate Cancer When XRCC1 Expression Is Reduced

Authors

Kaveri Goel
Vani Venkatappa
Kimiko L Krieger
Dongquan Chen
Arun Sreekumar
Natalie R Gassman

Language

English

Publication Date

6-1-2025

Journal

NAR Cancer

DOI

10.1093/narcan/zcaf015

PMID

40271221

PMCID

PMC12015684

PubMedCentral® Posted Date

4-23-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Prostate cancer (PCa) is the second most common cancer worldwide and the fifth leading cause of cancer-related deaths among men. The emergence of metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) exemplifies the complex disease management for PCa. PARP inhibitors (PARPis) are being tested to treat mCRPC in tumors with defective homologous recombination repair (HRR) to address this complexity. However, increasing resistance towards PARPi in HRR-deficient patients and the low percentage of HRR-defective mCRPC patients requires the identification of new genes whose deficiency can be exploited for PARPi treatment. XRCC1 is a DNA repair protein critical in the base excision repair (BER) and single strand break repair (SSBR) pathways. We analyzed PCa patients' cohorts and found that XRCC1 expression varies widely, with many patients showing low XRCC1 expression. We created XRCC1 deficiency in PCa models to examine PARPi sensitivity. XRCC1 loss conferred hypersensitivity to PARPi by promoting the accumulation of DNA double-strand breaks, increasing cell-cycle arrest, and inducing apoptosis. We confirmed that XRCC1 expression correlated with PARPi sensitivity using a doxycycline-inducible system. Therefore, we conclude that XRCC1 expression level predicts response to PARPi, and the clinical utility of PARPi in PCa can extend to low XRCC1 expressing tumors.

Keywords

Male, X-ray Repair Cross Complementing Protein 1, Humans, Poly(ADP-ribose) Polymerase Inhibitors, Prostatic Neoplasms, Castration-Resistant, Apoptosis, Prostatic Neoplasms, Cell Line, Tumor, DNA Repair, Animals, Mice, DNA Breaks, Double-Stranded, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic

Published Open-Access

yes

Recommended Citation

Goel, Kaveri; Venkatappa, Vani; Krieger, Kimiko L; et al., "Parp Inhibitor Response Is Enhanced in Prostate Cancer When XRCC1 Expression Is Reduced" (2025). Faculty and Staff Publications. 4903.
https://digitalcommons.library.tmc.edu/baylor_docs/4903