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PARP inhibitor response is enhanced in prostate cancer when XRCC1 expression is reduced
Kaveri Goel1, Vani Venkatappa2, Kimiko L Krieger2
1Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, United States.
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.
Insights
Low expression of the DNA repair protein XRCC1 predicts prostate cancer (PCa) response to PARP inhibitors (PARPis). This finding expands potential PARPi treatment to more mCRPC patients with low XRCC1 levels.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer (PCa) is a leading cause of cancer death in men, with metastatic castration-resistant PCa (mCRPC) posing significant management challenges.
- Poly (ADP-ribose) polymerase inhibitors (PARPis) show promise for mCRPC, particularly in tumors with homologous recombination repair (HRR) defects.
- Resistance to PARPis and the limited number of HRR-defective mCRPC patients necessitate identifying new therapeutic targets.
Purpose of the Study:
- To investigate the role of XRCC1 (a DNA repair protein) in PARPi sensitivity in prostate cancer.
- To determine if low XRCC1 expression can predict response to PARP inhibitors (PARPis) in mCRPC.
Main Methods:
- Analysis of XRCC1 expression levels in prostate cancer patient cohorts.
- Generation of XRCC1-deficient prostate cancer models to assess PARPi sensitivity.
- Utilized a doxycycline-inducible system to confirm the correlation between XRCC1 expression and PARPi response.
Main Results:
- XRCC1 expression varies significantly in prostate cancer patients, with many exhibiting low levels.
- XRCC1 deficiency in PCa models led to hypersensitivity to PARPis, characterized by increased DNA double-strand breaks, cell-cycle arrest, and apoptosis.
- Confirmed a direct correlation between XRCC1 expression levels and sensitivity to PARPi treatment.
Conclusions:
- XRCC1 expression level is a predictive biomarker for PARPi response in prostate cancer.
- The clinical application of PARPis can be extended to prostate cancer patients with low XRCC1 expression.
- Targeting XRCC1 deficiency offers a potential strategy to overcome PARPi resistance in mCRPC.
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