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Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated.

Author	Richard D Kennedy, Clark C Chen, Patricia Stuckert, Elyse M Archila, Michelle A De la Vega, Lisa A Moreau, Akiko Shimamura,
Citation Information	The Journal of clinical investigation, 117:1440-9 (2007)
Keywords	Animals, Cell Cycle Proteins, Cell Line, Transformed, Cell Line, Tumor, Cells, Cultured, DNA Damage, DNA-Binding Proteins, Fanconi Anemia, Fanconi Anemia Complementation Group C Protein, Fanconi Anemia Complementation Group G Protein, Hela Cells, Humans, Mice, Mice, Knockout, Protein-Serine-Threonine Kinases, Signal Transduction, Tumor Suppressor Proteins
Related Products	07-164
Pub Med ID	17431503

The Fanconi anemia (FA) pathway maintains genomic stability in replicating cells. Some sporadic breast, ovarian, pancreatic, and hematological tumors are deficient in FA pathway function, resulting in sensitivity to DNA-damaging agents. FA pathway dysfunction in these tumors may result in hyperdependence on alternative DNA repair pathways that could be targeted as a treatment strategy. We used a high-throughput siRNA screening approach that identified ataxia telangiectasia mutated (ATM) as a critical kinase for FA pathway-deficient human fibroblasts. Human fibroblasts and murine embryonic fibroblasts deficient for the FA pathway were observed to have constitutive ATM activation and Fancg(-/-)Atm(-/-) mice were found to be nonviable. Abrogation of ATM function in FA pathway-deficient cells resulted in DNA breakage, cell cycle arrest, and apoptotic cell death. Moreover, Fanconi anemia complementation group G- (FANCG-) and FANCC-deficient pancreatic tumor lines were more sensitive to the ATM inhibitor KU-55933 than isogenic corrected lines. These data suggest that ATM and FA genes function in parallel and compensatory roles to maintain genomic integrity and cell viability. Pharmaceutical inhibition of ATM may have a role in the treatment of FA pathway-deficient human cancers.