PTEN-Deficient Tumor Cells Are Dependent on ATM Signaling

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. Cancer Res; 75(11); 2159–65. ©2015 AACR.

Source: Cancer Research - May 31, 2015 Category: Cancer & Oncology Authors: McCabe, N., Hanna, C., Walker, S. M., Gonda, D., Li, J., Wikstrom, K., Savage, K. I., Butterworth, K. T., Chen, C., Harkin, D. P., Prise, K. M., Kennedy, R. D. Tags: Priority Reports Source Type: research