Ruiz, SergioMayor-Ruiz, CristinaLafarga, VanesaMurga, MatildeVega-Sendino, MariaOrtega Jimenez, SagrarioFernandez-Capetillo, Oscar2019-10-232019-10-232016-04-21Mol Cell. 2016;62(2):307-313.10972765http://hdl.handle.net/20.500.12105/8526One 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.engAMhttp://creativecommons.org/licenses/by-nc-sa/4.0/Antineoplastic AgentsAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsCell LineDose-Response Relationship, DrugDrug Resistance, NeoplasmEmbryonic Stem CellsGenome-Wide Association StudyHumansMitosisMolecular Targeted TherapyNuclear ProteinsProtein Kinase InhibitorsProtein-Tyrosine KinasesRNA InterferenceSignal TransductionTransfectioncdc25 PhosphatasesCRISPR-Cas SystemsAtribución-NoComercial-CompartirIgual 4.0 Internacional27067599622307-31310.1016/j.molcel.2016.03.0061097-4164Molecular cellopen access