The efficacy and toxicity of ATM inhibition in glioblastoma initiating cells-driven tumor models

Crit Rev Oncol Hematol. 2019 Jun:138:214-222. doi: 10.1016/j.critrevonc.2019.04.015. Epub 2019 Apr 21.

Abstract

The Ataxia Telangiectasia Mutated (ATM)-mediated DNA damage response (DDR) is a major mechanism of resistance of glioblastoma (GB) - initiating cells (GICs) to radiotherapy. The closely related Ataxia Telangiectasia and Rad3-related protein (ATR) is also involved in tumor resistance to radio- and chemotherapy. It has been shown that pharmacological inhibition of ATM protein may overcome the DDR-mediated resistance in GICs and significantly radiosensitize GIC-driven GB. Albeit not essential for life as shown by the decade-long lifespan of AT patients, the ATM protein may be involved in a number of important functions other than the response to DNA damage. We discuss our current knowledge about the toxicity of pharmacologic inhibition of ATM and ATR proteins.

Keywords: Animal models; Ataxia telangiectasia mutated; Glioma initiating cells; High grade glioma; Side effects.

Publication types

  • Review

MeSH terms

  • Adult
  • Animals
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • Brain Neoplasms / pathology*
  • DNA Damage / drug effects
  • Glioblastoma / pathology*
  • Humans
  • Neoplastic Stem Cells / drug effects
  • Radiation Tolerance / drug effects
  • Radiation-Sensitizing Agents / pharmacology*

Substances

  • Radiation-Sensitizing Agents
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins