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Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR

Abstract

Here we report a comprehensive biological characterization of a potent and selective small-molecule inhibitor of the DNA damage response (DDR) kinase ATR. We show a profound synthetic lethal interaction between ATR and the ATM-p53 tumor suppressor pathway in cells treated with DNA-damaging agents and establish ATR inhibition as a way to transform the outcome for patients with cancer treated with ionizing radiation or genotoxic drugs.

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Figure 1: ATR inhibition selectively sensitizes cancer cells to cisplatin.
Figure 2: Synthetic lethality between ATR and ATM-p53 in cisplatin-treated cells.

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Acknowledgements

We thank A. Peek, S. Falcon, M. Mangan, H. Sundaram and P. Weber for support with cell screening studies; P. Wang and J. Westcott for support with biochemical studies; R. Long for help generating the final figures and the full ATR project team for efforts leading to VE-821.

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Authors

Contributions

P.M.R. conceived, supervised and evaluated the experiments with support from J.R.P., P.A.C. and J.M.C.G. J.M.L. contributed key reagents and to the cell signaling experiments. All other experiments were performed by P.M.R. and M.R.G. J.-D.C. and S.M. conceived the synthetic route to, and prepared, VE-821 with help from J.M.C.G. P.M.R. and J.R.P. wrote the paper with support from J.-D.C., P.A.C. and J.M.C.G.

Corresponding author

Correspondence to John R Pollard.

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Competing interests

All authors are full time employees of Vertex Pharmaceuticals (Europe), Ltd. and hold equity in Vertex Pharmaceuticals, Inc.

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Supplementary Results, Supplementary Discussion and Supplementary Methods (PDF 6279 kb)

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Reaper, P., Griffiths, M., Long, J. et al. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 7, 428–430 (2011). https://doi.org/10.1038/nchembio.573

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