Journal
DNA REPAIR
Volume 26, Issue -, Pages 54-64Publisher
ELSEVIER
DOI: 10.1016/j.dnarep.2014.12.003
Keywords
PARP inhibitor; Fanconi anemia; Warsaw breakage syndrome; Sister chromatid cohesion; FANCM; DDX11
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Funding
- Cancer Center Amsterdam (CCA)
- Fanconi Anemia Research Fund (FARF), Portland, OR, U.S.A
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The encouraging response rates of BRCA1- and BRCA2-mutated cancers toward PARP inhibitors make it worthwhile to identify other potential determinants of PARP inhibitor responsiveness. Since the Fanconi anemia (FA) pathway coordinates several DNA repair pathways, including homologous recombination in which BRCA1 and BRCA2 play important roles, we investigated whether this pathway harbors other predictors of PARP inhibitor sensitivity. Lymphoblastoid cell lines derived from individuals with FA or clinically related syndromes, such as Warsaw breakage syndrome, were tested for PARP inhibitor sensitivity. Remarkably, we found a strong variability in PARP inhibitor sensitivity among different FANCD1/BRCA2-deficient lymphoblasts, suggesting that PARP inhibitor response depends on the type of FANCD1/BRCA2 mutation. We identified the DNA helicases FANCM and DDX11 as determinants of PARP inhibitor response. These results may extend the utility of PARP inhibition as effective anticancer treatment. (C) 2014 Elsevier B.V. All rights reserved.
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