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Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival

Deborah Wilsker1, Jon H Chung, Ivan Pradilla

  • 1Department of Radiation Oncology and Molecular Radiation Sciences and The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

Molecular Cancer Therapeutics
|November 16, 2011
PubMed

Insights

Targeting the Cdk2/ATR/Chk1 pathway with anticancer agents can sensitize cancer cells. Inhibiting specific regulators of this DNA damage response pathway offers a novel therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • Anticancer agents often induce DNA damage, triggering cellular responses.
  • The ataxia-telangiectasia mutated and Rad 3-related (ATR) pathway is crucial for signaling DNA damage and activating survival mechanisms.
  • ATR is a promising therapeutic target to enhance existing cancer treatments.

Purpose of the Study:

  • To investigate the roles of upstream and downstream components of the ATR pathway in cancer cell response to therapeutic agents.
  • To determine how cyclin-dependent kinase 2 (Cdk2) and checkpoint kinase 1 (Chk1) influence ATR pathway activation and downstream signaling.
  • To assess the potential of targeting the Cdk2/ATR/Chk1 axis for cancer therapy.

Main Methods:

  • Utilized a unique panel of genetically modified human cancer cells.
  • Examined the activation of ATR in response to various chemotherapeutic agents.
  • Assessed the requirement of Cdk2 for ATR activation and Chk1 signaling.
  • Evaluated the impact of pathway inhibition on cancer cell survival.

Main Results:

  • S-phase-specific cyclin-dependent kinase 2 (Cdk2) was essential for robust ATR activation by chemotherapeutic agents.
  • Cdk2-mediated ATR activation contributed to cell survival following treatment with numerous drugs.
  • ATR signaling to checkpoint kinase 1 (Chk1) was necessary for survival responses to only a subset of the tested drugs.
  • Distinct regulators within the Cdk2/ATR/Chk1 pathway differentially impact cancer cell sensitivity.

Conclusions:

  • The Cdk2/ATR/Chk1 pathway plays a differential role in cancer cell survival depending on the therapeutic agent.
  • Targeting specific components of the Cdk2/ATR/Chk1 pathway can selectively sensitize cancer cells to anticancer drugs.
  • This pathway represents a viable target for developing novel therapeutic strategies to potentiate chemotherapy.

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