TY - JOUR
T1 - Mechanistic rationale to target PTEN-deficient tumor cells with inhibitors of the DNA damage response kinase ATM
AU - McCabe, Nuala
AU - Hanna, Conor
AU - Walker, Steven M.
AU - Gonda, David
AU - Li, Jie
AU - Wikstrom, Katarina
AU - Savage, Kienan I.
AU - Butterworth, Karl T.
AU - Chen, Clark
AU - Harkin, D. Paul
AU - Prise, Kevin M.
AU - Kennedy, Richard D.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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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U2 - 10.1158/0008-5472.CAN-14-3502
DO - 10.1158/0008-5472.CAN-14-3502
M3 - Article
C2 - 25870146
AN - SCOPUS:84939451678
VL - 75
SP - 2159
EP - 2165
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -