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Inhibition of the ATR-DNAPKcs-RB axis drives G1/S-phase transition and sensitizes triple-negative breast cancer

Yue-Miao Hu1, Xue-Cun Liu1, Lei Hu1

  • 1School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Basic Science Research Center Base (Pharmaceutical Science), Yantai University, Yantai 264005, China.

Biochemical Pharmacology
|May 24, 2024
PubMed

Insights

Targeting the DNA damage response (DDR) with ATR inhibitors shows promise for treating triple-negative breast cancer (TNBC). This approach disrupts cell cycle progression and induces lethal damage, offering a new therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The DNA damage response (DDR) is a critical pathway in cancer therapy, exploiting tumor cell repair defects.
  • Ataxia telangiectasia mutated and RAD3-related protein (ATR) is a key sensor in the DDR pathway with potential therapeutic applications.
  • Triple-negative breast cancer (TNBC) presents unique challenges, necessitating novel treatment strategies.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting ATR in cancer treatment.
  • To identify a novel molecular axis regulated by ATR inhibitors.
  • To explore the efficacy of ATR inhibition in both RB-positive and RB-deficient TNBC cells.

Main Methods:

  • Utilized ATR inhibitors to target cancer cells.
  • Investigated the modulation of DNA-dependent protein kinase catalytic subunit (DNAPKcs) and retinoblastoma (RB) expression.
  • Analyzed the formation of four-way DNA Holliday junctions (FJs) and their role in cell cycle arrest.
  • Assessed the impact of inhibiting homologous recombination repair (HRR) in conjunction with ATR inhibition.

Main Results:

  • ATR inhibition led to decreased DNA-dependent protein kinase catalytic subunit (DNAPKcs) and downregulated retinoblastoma (RB) expression, promoting G1/S-phase transition.
  • The assembly of four-way DNA Holliday junctions (FJs) induced S-phase arrest and lethal chromosome damage in RB-positive TNBC cells.
  • Unrepaired FJs caused toxicity in RB-deficient TNBC cells when homologous recombination repair (HRR) was inhibited.

Conclusions:

  • Targeting ATR presents a precise strategy for treating TNBC by manipulating the DDR.
  • The study elucidates a novel mechanism involving ATR, DNA-PKcs, RB, and Holliday junctions in cancer therapy.
  • This research expands the understanding of ATR and Holliday junction roles in tumor treatment, offering new therapeutic avenues for TNBC.
Keywords:
Ataxia Telangiectasia and Rad3-related proteinCell cycleDNA Holliday junctionRetinoblastomaTriple Negative Breast Cancer

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