title: A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors.
abstract: One recurring theme in drug development is to exploit synthetic lethal properties as means to preferentially damage the DNA of cancer cells. We and others have previously developed inhibitors of the ATR kinase, shown to be particularly genotoxic for cells expressing certain oncogenes. In contrast, the mechanisms of resistance to ATR inhibitors remain unexplored. We report here on a genome-wide CRISPR-Cas9 screen that identified CDC25A as a major determinant of sensitivity to ATR inhibition. CDC25A-deficient cells resist high doses of ATR inhibitors, which we show is due to their failure to prematurely enter mitosis in response to the drugs. Forcing mitotic entry with WEE1 inhibitors restores the toxicity of ATR inhibitors in CDC25A-deficient cells. With ATR inhibitors now entering the clinic, our work provides a better understanding of the mechanisms by which these compounds kill cells and reveals genetic interactions that could be used for their rational use.
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: sruizm@cnio.es.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mayor-Ruiz
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Lafarga
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Vega-Sendino
authors.affiliation: Transgenics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 21 Stockholm, Sweden. Electronic address: ofernandez@cnio.es.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D064113:CRISPR-Cas Systems; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D055106:Genome-Wide Association Study; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; C576897:Atr protein, mouse; D011505:Protein-Tyrosine Kinases; C499348:Wee1 protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases