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Mol Cell. 2016 Apr 21;62(2):307-313. doi: 10.1016/j.molcel.2016.03.006. Epub 2016 Apr 7.

A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors.

Author information

1
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: sruizm@cnio.es.
2
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
3
Transgenics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
4
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.

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.

PMID:
27067599
PMCID:
PMC5029544
DOI:
10.1016/j.molcel.2016.03.006
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

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