2. Academic Validation
  3. Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM

Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM

  • Cancer Res. 2015 Jun 1;75(11):2159-65. doi: 10.1158/0008-5472.CAN-14-3502.
Nuala McCabe 1,  Conor Hanna 2,  Steven M Walker 1,  David Gonda 3,  Jie Li 3,  Katarina Wikstrom 4,  Kienan I Savage 2,  Karl T Butterworth 2,  Clark Chen 3,  D Paul Harkin 1,  Kevin M Prise 5,  Richard D Kennedy 6
Affiliations

Affiliations

  • 1 Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom. Almac Diagnostics, Craigavon, Northern Ireland, United Kingdom.
  • 2 Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom.
  • 3 University of California, San Diego, La Jolla, California.
  • 4 Almac Diagnostics, Craigavon, Northern Ireland, United Kingdom.
  • 5 Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom. r.kennedy@qub.ac.uk k.prise@qub.ac.uk.
  • 6 Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom. Almac Diagnostics, Craigavon, Northern Ireland, United Kingdom. r.kennedy@qub.ac.uk k.prise@qub.ac.uk.
PMID: 25870146 DOI: 10.1158/0008-5472.CAN-14-3502
Abstract

Ataxia telangiectasia mutated (ATM) is an important signaling molecule in the DNA damage response (DDR). ATM loss of function can produce a synthetic lethal phenotype in combination with tumor-associated mutations in FA/BRCA pathway components. In this study, we took an siRNA screening strategy to identify other tumor suppressors that, when inhibited, similarly sensitized cells to ATM inhibition. In this manner, we determined that PTEN and ATM were synthetically lethal when jointly inhibited. PTEN-deficient cells exhibited elevated levels of Reactive Oxygen Species, increased endogenous DNA damage, and constitutive ATM activation. ATM inhibition caused catastrophic DNA damage, mitotic cell cycle arrest, and Apoptosis specifically in PTEN-deficient cells in comparison with wild-type cells. Antioxidants abrogated the increase in DNA damage and ATM activation in PTEN-deficient cells, suggesting a requirement for oxidative DNA damage in the mechanism of cell death. Lastly, the ATM Inhibitor KU-60019 was specifically toxic to PTEN mutant Cancer cells in tumor xenografts and reversible by reintroduction of wild-type PTEN. Together, our results offer a mechanistic rationale for clinical evaluation of ATM inhibitors in PTEN-deficient tumors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12061
    99.43%, ATM/ATR Inhibitor