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ATR mediates cisplatin resistance in a p53 genotype-specific manner

N Sangster-Guity1, B H Conrad, N Papadopoulos

  • 1Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Oncogene
|January 25, 2011
PubMed

Insights

Inhibiting ATR enhances cisplatin sensitivity in colorectal cancer cells lacking p53. Restoring p53 function in ATR-deficient cells improves survival, suggesting combined ATR inhibitors and therapies for p53-deficient tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Ataxia telangiectasia and Rad3-related (ATR) kinase is crucial for DNA damage response.
  • ATR inhibitors are explored as anticancer agents, potentially sensitizing tumors to chemotherapy.
  • Cisplatin is effective but causes significant toxicity, limiting its clinical use.

Purpose of the Study:

  • To investigate the effect of ATR inhibition on cisplatin sensitivity in colorectal cancer cells.
  • To determine the role of p53 status in ATR-mediated chemosensitization.
  • To explore the potential for synthetic lethality strategies combining ATR inhibition and cisplatin.

Main Methods:

  • Genetic inhibition of ATR expression in human colorectal cancer cell lines.
  • Utilizing a knock-in strategy to restore wild-type p53 function.
  • Assessing cisplatin sensitivity, checkpoint function, apoptosis, and clonogenic survival.

Main Results:

  • Genetic ATR inhibition selectively enhanced cisplatin sensitivity in p53-deficient colorectal cancer cells.
  • Restoration of wild-type p53 in ATR-deficient cells re-established checkpoint control and suppressed apoptosis.
  • Functional p53 significantly increased clonogenic survival following cisplatin treatment in ATR-deficient cells.

Conclusions:

  • ATR inhibition combined with cisplatin shows promise for selectively targeting p53-deficient tumors.
  • This approach may lead to synthetic lethality, enhancing efficacy while reducing normal tissue toxicity.
  • Targeting ATR offers a potential strategy to overcome cisplatin resistance and toxicity in specific cancer contexts.

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