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

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.

• Authors: Nuala McCabe, Conor Hanna, Steven M Walker, David Gonda, Jie Li, Katarina Wikstrom, Kienan I Savage, Karl T Butterworth, Clark Chen, D Paul Harkin, Kevin M Prise, Richard D Kennedy
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 11 Pg. 2159-65 (Jun 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25870146 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• 2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide
• Morpholines
• RNA, Small Interfering
• Thioxanthenes
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Apoptosis (drug effects)
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, genetics)
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• DNA Damage (drug effects)
• DNA Repair (drug effects)
• HCT116 Cells
• Heterografts
• Humans
• Mice
• Mitosis (drug effects)
• Morpholines (administration & dosage)
• PTEN Phosphohydrolase (biosynthesis, genetics)
• RNA, Small Interfering
• Thioxanthenes (administration & dosage)