ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen receptor (AR) signaling is crucial for prostate cancer progression.
• AR inactivation leads to rapid telomere dysfunction in prostate cancer cells.
• Telomere dysfunction typically activates DNA damage response (DDR) pathways.

Purpose of the Study:

• To investigate the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells.
• To determine if inhibiting ATM can enhance the efficacy of AR-targeted therapies.

Main Methods:

• Treatment of prostate cancer cells with AR antagonists (Casodex, MDV3100) or AR-siRNA.
• Assessment of ATM and Chk2 phosphorylation, and ATM localization at telomeres.
• Evaluation of telomere dysfunction reversal upon drug washout.
• Treatment with an ATM inhibitor and assessment of apoptosis markers (PARP cleavage, γH2AX foci) and cell cycle checkpoints.
• Colony formation assays to assess cell survival.

Main Results:

• AR inactivation induced telomere dysfunction and activated ATM-mediated DDR signaling at telomeres.
• ATM inhibitor treatment in AR-inactivated cells led to apoptosis by blocking DNA repair at telomeres.
• Combined treatment with Casodex and an ATM inhibitor significantly reduced cell survival compared to single treatments.

Conclusions:

• ATM-mediated DDR signaling is activated by telomere dysfunction upon AR inactivation in prostate cancer.
• Inhibiting ATM enhances the apoptotic effects of AR-targeted therapy in prostate cancer cells.
• Targeting DDR signaling pathways presents a potential strategy to improve AR-targeted therapies for all stages of prostate cancer.