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Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation.

Publication ,  Journal Article
Rainey, MD; Charlton, ME; Stanton, RV; Kastan, MB
Published in: Cancer Res
September 15, 2008

In response to DNA damage, the ATM protein kinase activates signal transduction pathways essential for coordinating cell cycle progression with DNA repair. In the human disease ataxia-telangiectasia, mutation of the ATM gene results in multiple cellular defects, including enhanced sensitivity to ionizing radiation (IR). This phenotype highlights ATM as a potential target for novel inhibitors that could be used to enhance tumor cell sensitivity to radiotherapy. A targeted compound library was screened for potential inhibitors of the ATM kinase, and CP466722 was identified. The compound is nontoxic and does not inhibit phosphatidylinositol 3-kinase (PI3K) or PI3K-like protein kinase family members in cells. CP466722 inhibited cellular ATM-dependent phosphorylation events and disruption of ATM function resulted in characteristic cell cycle checkpoint defects. Inhibition of cellular ATM kinase activity was rapidly and completely reversed by removing CP466722. Interestingly, clonogenic survival assays showed that transient inhibition of ATM is sufficient to sensitize cells to IR and suggests that therapeutic radiosensitization may only require ATM inhibition for short periods of time. The ability of CP466722 to rapidly and reversibly regulate ATM activity provides a new tool to ask questions about ATM function that could not easily be addressed using genetic models or RNA interference technologies.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 15, 2008

Volume

68

Issue

18

Start / End Page

7466 / 7474

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Triazoles
  • Signal Transduction
  • Radiation Tolerance
  • Quinazolines
  • Proto-Oncogene Proteins c-abl
  • Protein Serine-Threonine Kinases
  • Protein Kinase Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Oncology & Carcinogenesis
 

Citation

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Rainey, M. D., Charlton, M. E., Stanton, R. V., & Kastan, M. B. (2008). Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res, 68(18), 7466–7474. https://doi.org/10.1158/0008-5472.CAN-08-0763
Rainey, Michael D., Maura E. Charlton, Robert V. Stanton, and Michael B. Kastan. “Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation.Cancer Res 68, no. 18 (September 15, 2008): 7466–74. https://doi.org/10.1158/0008-5472.CAN-08-0763.
Rainey MD, Charlton ME, Stanton RV, Kastan MB. Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res. 2008 Sep 15;68(18):7466–74.
Rainey, Michael D., et al. “Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation.Cancer Res, vol. 68, no. 18, Sept. 2008, pp. 7466–74. Pubmed, doi:10.1158/0008-5472.CAN-08-0763.
Rainey MD, Charlton ME, Stanton RV, Kastan MB. Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res. 2008 Sep 15;68(18):7466–7474.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 15, 2008

Volume

68

Issue

18

Start / End Page

7466 / 7474

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Triazoles
  • Signal Transduction
  • Radiation Tolerance
  • Quinazolines
  • Proto-Oncogene Proteins c-abl
  • Protein Serine-Threonine Kinases
  • Protein Kinase Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Oncology & Carcinogenesis