Journal
CANCER RESEARCH
Volume 75, Issue 11, Pages 2159-2165Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-3502
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Funding
- Invest NI through the European Sustainable Competitiveness Programme [ST263]
- European Regional Development Fund (ERDF)
- Prostate Cancer UK [S10-08]
- FASTMAN Centre, Movember Prostate Cancer Centre of Excellence [CE013_ 2-004]
- Medical Research Council [MR/K018965/1] Funding Source: researchfish
- Prostate Cancer UK [S10-08, CEO13_2-004] Funding Source: researchfish
- Public Health Agency [SPI/3315/06] Funding Source: researchfish
- MRC [MR/K018965/1] Funding Source: UKRI
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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. (C) 2015 AACR.
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