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Fanconi anemia pathway–deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated
Richard D. Kennedy, … , Akiko Shimamura, Alan D. D’Andrea
Richard D. Kennedy, … , Akiko Shimamura, Alan D. D’Andrea
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1440-1449. https://doi.org/10.1172/JCI31245.
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Research Article Oncology Article has an altmetric score of 6

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

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Abstract

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.

Authors

Richard D. Kennedy, Clark C. Chen, Patricia Stuckert, Elyse M. Archila, Michelle A. De la Vega, Lisa A. Moreau, Akiko Shimamura, Alan D. D’Andrea

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Frequency of genotypes of offspring from interbred Fancg+/–Atm+/– mice c...

Frequency of genotypes of offspring from interbred Fancg+/–Atm+/– mice compared with the predicted frequencies by Mendelian genetics


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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 4 patents
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