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Ref Type Journal Article
PMID (25870146)
Authors McCabe N, Hanna C, Walker SM, Gonda D, Li J, Wikstrom K, Savage KI, Butterworth KT, Chen C, Harkin DP, Prise KM, Kennedy RD
Title Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 75 11 2015 Jun 1 2159-65 Cancer Res
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN loss colon cancer sensitive KU-55933 Preclinical Actionable In a preclinical study, KU-55933 induced cell cycle arrest and caspase activation in PTEN deficient human colon cancer cells in culture (PMID: 25870146). 25870146
PTEN loss prostate cancer sensitive KU-60019 Preclinical Actionable In a preclinical study, KU-60019 blocked tumor growth in PTEN-deficient human prostate cancer xenograft models (PMID: 25870146). 25870146