title: 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: Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom. Almac Diagnostics, Craigavon, Northern Ireland, United Kingdom.
authors: Nuala
authors: N
authors: McCabe
authors: Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom.
authors: Conor
authors: C
authors: Hanna
authors: Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom. Almac Diagnostics, Craigavon, Northern Ireland, United Kingdom.
authors: Steven M
authors: SM
authors: Walker
authors: University of California, San Diego, La Jolla, California.
authors: David
authors: D
authors: Gonda
authors: University of California, San Diego, La Jolla, California.
authors: Jie
authors: J
authors: Li
authors: Almac Diagnostics, Craigavon, Northern Ireland, United Kingdom.
authors: Katarina
authors: K
authors: Wikstrom
authors: Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom.
authors: Kienan I
authors: KI
authors: Savage
authors: Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom.
authors: Karl T
authors: KT
authors: Butterworth
authors: University of California, San Diego, La Jolla, California.
authors: Clark
authors: C
authors: Chen
authors: Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom. Almac Diagnostics, Craigavon, Northern Ireland, United Kingdom.
authors: D Paul
authors: DP
authors: Harkin
authors: Centre for Cancer Research and Cell Biology, Queens University Belfast, Northern Ireland, United Kingdom. r.kennedy@qub.ac.uk k.prise@qub.ac.uk.
authors: Kevin M
authors: KM
authors: Prise
authors: 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.
authors: Richard D
authors: RD
authors: Kennedy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D045325:HCT116 Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009025:Morpholines / Q000008:administration & dosage; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering; D013892:Thioxanthenes / Q000008:administration & dosage
chemical_list: C546193:2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide; D009025:Morpholines; D034741:RNA, Small Interfering; D013892:Thioxanthenes; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human