Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling

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Styliani Karanika1, Theodoros Karantanos1, Likun Li1

  • 1Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cell Reports
|February 24, 2017
PubMed

Insights

Targeting Cell Division Cycle 6 (CDC6) and androgen receptor (AR) signaling with enzalutamide and AZD7762 shows promise for treating prostate cancer. This combination therapy effectively inhibits tumor growth and induces apoptosis in AR-positive models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cell division cycle 6 (CDC6) is an androgen receptor (AR) target gene involved in DNA replication and checkpoint control.
  • CDC6 expression and AR correlate positively in prostate cancer (PCa) and increase with disease progression.

Purpose of the Study:

  • To investigate the therapeutic potential of combining AR signaling inhibition with Chk1/2 inhibition in prostate cancer.
  • To evaluate the impact of targeting the AR-CDC6-ATR-Chk1 signaling pathway on treatment efficacy.

Main Methods:

  • Utilized AR or CDC6 knockdown combined with AZD7762 (Chk1/2 inhibitor).
  • Administered combination therapy of enzalutamide (ENZ) and AZD7762 in PCa cell lines (VCaP, LNCaP-C4-2b) and xenograft models.
  • Assessed TopBP1-ATR-Chk1 signaling, ATM phosphorylation, and apoptosis.

Main Results:

  • Combined AR/CDC6 knockdown with AZD7762 decreased AR-CDC6-ATR-Chk1 signaling and increased ATM phosphorylation, enhancing efficacy.
  • Combination of ENZ and AZD7762 showed synergistic effects on signaling inhibition, ATM phosphorylation, and apoptosis in both mutant and wild-type p53 PCa cells.
  • CDC6 overexpression attenuated apoptosis induced by ENZ and AZD7762.
  • Additive or synergistic effects were observed in AR-positive xenograft models.

Conclusions:

  • Targeting the AR-CDC6-ATR-Chk1 pathway with combined enzalutamide and AZD7762 offers a novel therapeutic strategy for AR-positive metastatic castration-resistant prostate cancer.
  • This approach is effective regardless of p53 mutation status.
  • Findings support clinical translation for advanced prostate cancer treatment.
Keywords:
ATRAZD7762CDC6Chk1DNA damageTOPBP1androgen receptorenzalutamideprostate cancer

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