American Association for Cancer Research
00085472can143502-sup-141710_1_supp_2877827_nkdpmy.pptx (31.03 MB)

Supplementary Figures 1-4 from Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM

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posted on 2023-03-30, 23:13 authored by Nuala McCabe, Conor Hanna, Steven M. Walker, David Gonda, Jie Li, Katarina Wikstrom, Kienan I. Savage, Karl T. Butterworth, Clark Chen, D. Paul Harkin, Kevin M. Prise, Richard D. Kennedy

Supplementary Figures 1-4. Figure 1: ATM is a potential drug target for PTEN-deficient cells Figure 2: The synthetic lethality with PTEN loss and ATM inhibition is independent of AKT function Figure 3: The synthetic lethality with PTEN loss and ATM inhibition is independent of RAD51 function Supplementary Figure 4: In vivo efficacy of ATM inhibition with PTEN loss



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

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