2026-07-21T07:35:38Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/85262024-11-29T18:25:57Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Ruiz, Sergio
author
Mayor-Ruiz, Cristina
author
Lafarga, Vanesa
author
Murga, Matilde
author
Vega-Sendino, Maria
author
Ortega Jimenez, Sagrario
author
Fernandez-Capetillo, Oscar
funder
Botín Foundation
funder
Fundación La Marató TV3
funder
Howard Hughes Medical Institute
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Fundación La Caixa
funder
Ministerio de Economía y Competitividad (España)
2019-10-23T08:56:27Z
2019-10-23T08:56:27Z
2016-04-21
Mol Cell. 2016;62(2):307-313.
10.1016/j.molcel.2016.03.006
1097-4164
10972765
Molecular cell
27067599
http://hdl.handle.net/20.500.12105/8526
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.
eng
A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors
journal article
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