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Updated: Jun 10, 2025
07:25
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
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Inhibition of Androgen Receptor Exposes Replication Stress Vulnerability in Prostate Cancer.
Biorxiv : the Preprint Server for Biology
|October 17, 2024
Summary
Androgen receptor pathway inhibitors (ARPIs) for metastatic prostate cancer cause DNA replication stress. Combining enzalutamide with a translesion DNA synthesis inhibitor, JH-RE-06, effectively suppresses tumor growth by exploiting this vulnerability.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Metastatic prostate cancer treatment commonly involves androgen receptor (AR) signaling inhibitors.
- Acquired resistance to AR pathway inhibitors (ARPIs) is a major clinical challenge.
- Standard ARPIs like enzalutamide are effective initially but resistance develops.
Purpose of the Study:
- To investigate the molecular mechanisms underlying resistance to ARPIs in prostate cancer.
- To explore the potential of targeting DNA replication stress and translesion DNA synthesis (TLS) in combination therapy.
- To evaluate the efficacy of combining enzalutamide with a TLS inhibitor.
Main Methods:
- Treatment of AR-positive prostate cancer cells with enzalutamide to induce DNA replication stress.
- Assessment of single-stranded DNA (ssDNA) gaps and DNA damage biomarkers.
- In vitro testing of the TLS inhibitor JH-RE-06 in combination with enzalutamide.
- Evaluation of combination therapy efficacy in a syngeneic murine tumor model.
Main Results:
- Enzalutamide treatment induces DNA replication stress in AR-positive prostate cancer cells.
- Suppression of translesion DNA synthesis (TLS) exacerbates this stress, leading to DNA damage.
- The TLS inhibitor JH-RE-06 sensitizes AR-positive prostate cancer cells to enzalutamide in vitro.
- Combination therapy significantly suppressed tumor growth in a preclinical mouse model.
Conclusions:
- Androgen receptor inhibition triggers DNA replication stress in hormone-sensitive prostate cancer.
- Targeting translesion DNA synthesis (TLS) represents a viable adjuvant strategy for ARPI therapy.
- Combination of enzalutamide with a TLS inhibitor offers a promising therapeutic approach for metastatic prostate cancer.
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