Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/8526
Título
A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors
Autor(es)
Ruiz, Sergio | Mayor-Ruiz, Cristina CNIO | Lafarga, Vanesa CNIO | Murga, Matilde CNIO | Vega-Sendino, Maria | Ortega Jimenez, Sagrario CNIO | Fernandez-Capetillo, Oscar CNIO
Fecha de publicación
2016-04-21
Cita
Mol Cell. 2016;62(2):307-313.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
MESH
Antineoplastic Agents | Ataxia Telangiectasia Mutated Proteins | Cell Cycle Proteins | Cell Line | Dose-Response Relationship, Drug | Drug Resistance, Neoplasm | Embryonic Stem Cells | Genome-Wide Association Study | Humans | Mitosis | Molecular Targeted Therapy | Nuclear Proteins | Protein Kinase Inhibitors | Protein-Tyrosine Kinases | RNA Interference | Signal Transduction | Transfection | cdc25 Phosphatases | CRISPR-Cas Systems
Versión en línea
DOI
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