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DNA Repair (Amst). 2015 Apr;28:107-15. doi: 10.1016/j.dnarep.2015.01.011. Epub 2015 Feb 11.

Alterations of DNA repair genes in the NCI-60 cell lines and their predictive value for anticancer drug activity.

Author information

1
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica, Programa de Pós-Graduação em Farmácia, Universidade Federal de Mato Grosso do Sul, Campo Grande 79070-900, MS, Brazil.
2
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
3
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Computational Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
4
Computational Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
5
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; HiThru Analytics LLC, Laurel, MD 20707, USA.
6
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: pommier@nih.gov.

Abstract

Loss of function of DNA repair (DNAR) genes is associated with genomic instability and cancer predisposition; it also makes cancer cells reliant on a reduced set of DNAR pathways to resist DNA-targeted therapy, which remains the core of the anticancer armamentarium. Because the landscape of DNAR defects across numerous types of cancers and its relation with drug activity have not been systematically examined, we took advantage of the unique drug and genomic databases of the US National Cancer Institute cancer cell lines (the NCI-60) to characterize 260 DNAR genes with respect to deleterious mutations and expression down-regulation; 169 genes exhibited a total of 549 function-affecting alterations, with 39 of them scoring as putative knockouts across 31 cell lines. Those mutations were compared to tumor samples from 12 studies of The Cancer Genome Atlas (TCGA) and The Cancer Cell Line Encyclopedia (CCLE). Based on this compendium of alterations, we determined which DNAR genomic alterations predicted drug response for 20,195 compounds present in the NCI-60 drug database. Among 242 DNA damaging agents, 202 showed associations with at least one DNAR genomic signature. In addition to SLFN11, the Fanconi anemia-scaffolding gene SLX4 (FANCP/BTBD12) stood out among the genes most significantly related with DNA synthesis and topoisomerase inhibitors. Depletion and complementation experiments validated the causal relationship between SLX4 defects and sensitivity to raltitrexed and cytarabine in addition to camptothecin. Therefore, we propose new rational uses for existing anticancer drugs based on a comprehensive analysis of DNAR genomic parameters.

KEYWORDS:

Cancer; Cytarabine; DNA repair; NCI-60; Raltitrexed; SLX4/FANCP/BTBD12

PMID:
25758781
PMCID:
PMC4385398
DOI:
10.1016/j.dnarep.2015.01.011
[Indexed for MEDLINE]
Free PMC Article

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