title: Alterations of DNA repair genes in the NCI-60 cell lines and their predictive value for anticancer drug activity.
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.
authors.affiliation: 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.
authors.forename: Fabricio G
authors.initials: FG
authors.lastname: Sousa
authors.affiliation: 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.
authors.forename: Renata
authors.initials: R
authors.lastname: Matuo
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Sai-Wen
authors.initials: SW
authors.lastname: Tang
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Vinodh N
authors.initials: VN
authors.lastname: Rajapakse
authors.affiliation: 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.
authors.forename: Augustin
authors.initials: A
authors.lastname: Luna
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: 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.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Varma
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Paul H G
authors.initials: PH
authors.lastname: Simon
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Reinhold
authors.affiliation: 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.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics*; D015536:Down-Regulation; D005796:Genes; D006801:Humans; D009154:Mutation; D054547:National Cancer Institute (U.S.); D014481:United States
chemical_list: D000970:Antineoplastic Agents
keywords: Cancer; Cytarabine; DNA repair; NCI-60; Raltitrexed; SLX4/FANCP/BTBD12