期刊
MOLECULAR CELL
卷 62, 期 2, 页码 307-313出版社
CELL PRESS
DOI: 10.1016/j.molcel.2016.03.006
关键词
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资金
- Fundacion Botin, Banco Santander, through Santander Universities Global Division
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2011-23753, SAF2014-57791-REDC]
- Fundacio La Marato de TV3
- Howard Hughes Medical Institute
- European Research Council [ERC-617840]
- La Caixa Foundation
- MINECO [RYC2011-09242, SAF2013-49147P, SAF2013-44866-R]
- European FEDER funds
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.
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