Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM

Abstract

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. Ó2015 AACR.

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary (Review)

“…Investigators have unraveled a set of candidate gene targets hypothetically resulting in synthetic lethality. HNF, ARID1A, ATR, ATM, Chk1 and PTEN may be the key genes in CCC (18,32,47,52,55). Notably, the HNF-Chk1 axis was specifically upregulated in CCC (18).…”

“…siRNA screening strategies identified PTEN and ATM as synthetically lethal partners (55). One preclinical study demonstrated that ATM inhibition resulted in DNA damage, cell cycle arrest and apoptosis specifically in PTEN-deficient cells (55).…”

When the guardian becomes the enemy: Targeting ATM in PTEN-deficient cancers

“…PTEN-deficient cells were found to arrest in the mitotic part of the cell cycle and demonstrated DNA aberrations consistent with catastrophic DNA damage 7 that led to apoptotic cell death (Fig. 1).…”

“…Importantly, this toxic effect is specific to the cancer cell in that loss of ATM function or the FA/BRCA pathway alone is not lethal, a phenomenon referred to as "synthetic lethality." 6 In our current publication 7 we have extended this work to look for synthetic lethal interactions between ATM and other TSGs. We used siRNA screening to individually knockdown 178 TSGs in paired ATM functional and nonfunctional cell lines and identified potential synthetic lethal interactions.…”

“…The PTEN-deficient cell line was aggressive and rapidly grew into a tumor mass, but was significantly inhibited by administration of an ATM inhibitor compared to cells expressing wild-type PTEN. 7 From a mechanistic perspective, PTEN-deficient cells were found to have elevated levels of endogenous DNA damage and CONTACT Nuala McCabe nuala.mccabe@qub.ac.uk activation of ATM compared to PTEN wild-type cells. RAD51 is an important component of DSB repair through a process termed homologous recombination (HR).…”