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08:32
Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes
Published on: May 23, 2025
535
Targeting radioresistance and replication fork stability in prostate cancer
Xiangyi Li1, GuemHee Baek1, Suzanne Carreira2
1Department of Pathology, University of Texas (UT) Southwestern Medical Center, Dallas, Texas, USA.
JCI Insight
|March 29, 2022
Summary
Bromodomain and extraterminal (BET) inhibitors enhance radiation therapy and topoisomerase I inhibitors for prostate cancer treatment. These combinations overcome resistance by blocking DNA repair and disrupting replication fork stability in aggressive tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Bromodomain and extraterminal (BET) proteins regulate gene expression.
- BET inhibitors (BETi) show limited efficacy as monotherapy in castration-resistant prostate cancer (CRPC).
- Novel combinatorial strategies are needed to enhance BETi efficacy in CRPC.
Purpose of the Study:
- To investigate the efficacy of BET inhibitors in combination with radiation therapy (RT) and topoisomerase I inhibitors (TOP1i) for prostate cancer (PCa).
- To elucidate the mechanisms underlying the synergistic effects of these combinations.
- To explore the potential of these combinations for treating aggressive CRPC.
Main Methods:
- Utilized patient-derived explants and xenograft models of PCa.
- Assessed the impact of BETi combined with RT on tumor growth and radioresistance.
- Evaluated the synergistic effects of BETi (OTX015) and a novel TOP1 inhibitor (LMP400) in CRPC models.
- Analyzed DNA repair, replication fork stability, and TOP1/BET gene expression in patient tumors.
Main Results:
- BETi treatment enhanced RT efficacy and overcame radioresistance by inhibiting DNA repair.
- BETi synergized with TOP1 inhibitors to block tumor growth in aggressive CRPC xenografts by disrupting replication fork stability.
- TOP1 expression increased with PCa progression to CRPC and correlated with BET gene expression.
Conclusions:
- BET inhibitors represent a promising strategy for combination therapy in aggressive prostate cancer.
- Combining BETi with RT or TOP1i offers a rational approach to overcome treatment resistance.
- Targeting BET proteins and TOP1 warrants further investigation for advanced PCa treatment.
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