Related Experiment Video

Updated: Jun 10, 2025

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
07:25

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

13.0K

Inhibition of Androgen Receptor Exposes Replication Stress Vulnerability in Prostate Cancer

Carly S Williams, Xin Li, Hongjun Jang

    Biorxiv : the Preprint Server for Biology
    |October 17, 2024
    PubMed

    Insights

    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.

    More Related Videos

    Quantifying Replication Stress in Ovarian Cancer Cells Using Single-Stranded DNA Immunofluorescence06:25

    Quantifying Replication Stress in Ovarian Cancer Cells Using Single-Stranded DNA Immunofluorescence

    Published on: February 10, 2023

    2.0K
    Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel06:44

    Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel

    Published on: September 8, 2017

    13.3K

    Related Concept Videos

    Negative Regulator Molecules01:23

    Negative Regulator Molecules

    Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
    35.2K
    The DNA Replication Fork01:02

    The DNA Replication Fork

    An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork.   Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication...
    35.6K
    DNA Damage can Stall the Cell Cycle02:37

    DNA Damage can Stall the Cell Cycle

    In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
    9.1K
    mTOR Signaling and Cancer Progression03:03

    mTOR Signaling and Cancer Progression

    The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
    The mTOR pathway or the...
    3.8K
    Abnormal Proliferation02:23

    Abnormal Proliferation

    Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
    4.5K
    Inhibition of Cdk Activity02:34

    Inhibition of Cdk Activity

    The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
    4.7K