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ATM Inhibition Sensitizes Tumors to High-Dose Irradiation

Dennis Hallahan1

  • 1Washington University School of Medicine, St. Louis, Missouri. dhallahan@wustl.edu.

Cancer Research
|February 17, 2019
PubMed

Insights

Targeting ataxia-telangiectasia-mutated (ATM) in cancer cells enhances high-dose radiation therapy efficacy. Deleting ATM in tumor cells, not endothelial cells, eliminated lung tumors in mice, supporting ATM inhibitors in clinical trials.

Area of Science:

  • Oncology
  • Radiation Oncology
  • Molecular Biology

Background:

  • High-dose irradiation is a cornerstone of cancer treatment.
  • Understanding mechanisms to enhance radiotherapy efficacy is crucial.
  • Ataxia-telangiectasia-mutated (ATM) is a key DNA damage response protein.

Purpose of the Study:

  • To investigate the role of ATM in mediating resistance to high-dose irradiation.
  • To determine whether targeting ATM in cancer cells or endothelial cells impacts tumor response.

Main Methods:

  • Utilized a mouse model with targeted deletion of ATM in cancer cells or endothelial cells.
  • Administered a single 15 Gy dose of stereotactic irradiation to lung tumors.
  • Assessed tumor growth and elimination post-irradiation.

Main Results:

  • A single 15 Gy radiation dose eradicated lung tumors when ATM was deleted specifically in cancer cells.
  • Deletion of ATM in endothelial cells did not yield the same tumor elimination.
  • This highlights the differential role of ATM in tumor and stromal compartments.

Conclusions:

  • ATM deletion in cancer cells significantly sensitizes tumors to high-dose irradiation.
  • ATM inhibitors represent a promising therapeutic strategy to enhance radiotherapy outcomes.
  • Clinical trials combining ATM inhibitors with radiotherapy are warranted.

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