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When the guardian becomes the enemy: Targeting ATM in PTEN-deficient cancers

Nuala McCabe1, Steven M Walker1, Richard D Kennedy1

  • 1Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland; Almac Diagnostics, Craigavon, Northern Ireland.

Molecular & Cellular Oncology
|June 17, 2016
PubMed

Insights

Inhibiting Ataxia telangiectasia mutated (ATM) shows promise for treating cancers with phosphatase and tensin homolog (PTEN) loss. This approach leverages synthetic lethality driven by increased oxidative stress.

Area of Science:

  • Oncology
  • Molecular Biology
  • DNA Damage Response

Background:

  • Ataxia telangiectasia mutated (ATM) is a key protein in cellular responses to DNA damage.
  • ATM inhibitors are currently in clinical development for cancer therapy.
  • Phosphatase and tensin homolog (PTEN) loss is implicated in various cancers.

Purpose of the Study:

  • To investigate the therapeutic potential of ATM inhibition in PTEN-deficient cancers.
  • To elucidate the underlying mechanisms of synthetic lethality between ATM inhibition and PTEN loss.

Main Methods:

  • Utilized cell-based assays to assess the effects of ATM inhibition.
  • Quantified DNA damage and oxidative stress markers.
  • Employed genetic manipulation to study PTEN loss.

Main Results:

  • Identified a synthetic lethal interaction between ATM inhibition and PTEN loss.
  • Demonstrated that ATM inhibition leads to increased oxidative stress in PTEN-deficient cells.
  • Showcased the selective killing of PTEN-loss cancer cells upon ATM inhibition.

Conclusions:

  • ATM inhibition represents a novel synthetic lethal strategy for targeting PTEN-associated cancers.
  • The observed synthetic lethality is mediated by elevated oxidative stress.
  • This finding opens new avenues for PTEN-cancer therapeutic development.
Keywords:
ATMDNA damageDSBPTENROS

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