Defects in members of the FA DDR pathway have an established association with inherited predisposition to cancer, in the form of FA itself or BRCA2 heterozygosity, and are increasingly associated with sporadic cancers. The authors used a small interfering RNA (siRNA) library, which targets 230 DDR genes, to identify genes that confer survival in FA complementation group G (FANCG) cells, which are defective in FA pathway activity. They confirmed that the BER pathway is important for the survival of these cells; however, they also identified three members of the ataxia-telangiectasia mutated (ATM)-dependent DDR pathway, including ATM itself. Indeed, ATM was active at a low level in FA cells. Surprisingly, they showed that Atm−/−; Fancg−/− mice are not viable, demonstrating that ATM-dependent and FA DDR pathways are essential for survival and function in parallel, despite previous data showing that ATM phosphorylates FANCD2, a component of the FA DDR pathway.
The authors showed that DNA breaks increased in FANCG cells that had been treated with ATM siRNA, indicating that ATM is required for the repair of spontaneous DNA breaks that occur in the absence of the FA pathway. Therefore, governed by the same rationale as the application of PARP1 inhibitors, D'Andrea and colleagues used the ATM-specific competitive inhibitor KU55933 to investigate whether FA pathway-deficient cells were more sensitive to ATM inhibition. They found that the drug significantly increased apoptosis in FA cell lines, and clonogenic survival assays showed that FA complementation group C (FANCC; also defective in the FA pathway) cells were more sensitive to KU55933 compared with controls. Moreover, they showed that FANCC- and FANCG-deficient human pancreatic cancer cell lines were sensitive to KU55933.
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