Abstract
The identification of the cellular targets of small molecules with anticancer activity is crucial to their further development as drug candidates. Here, we present the application of a large-scale RNA interference–based short hairpin RNA (shRNA) barcode screen to gain insight in the mechanism of action of nutlin-3 (1). Nutlin-3 is a small-molecule inhibitor of MDM2, which can activate the p53 pathway. Nutlin-3 shows strong antitumor effects in mice, with surprisingly few side effects on normal tissues1. Aside from p53, we here identify 53BP1 as a critical mediator of nutlin-3–induced cytotoxicity. 53BP1 is part of a signaling network induced by DNA damage that is frequently activated in cancer but not in healthy tissues2. Our results suggest that nutlin-3's tumor specificity may result from its ability to turn a cancer cell–specific property (activated DNA damage signaling3) into a weakness that can be exploited therapeutically.
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Acknowledgements
We thank the Netherlands Cancer Institute microarray facility group for assistance; K. Berns, S. Nijman, H. Ovaa and members of the Bernards and Beijersbergen laboratories for help and discussions; L. Oomen for help with confocal microscopy; and R. Kortlever for critically reading the manuscript. This work was supported by grants from the Dutch Cancer Society (KWF) and the European Union integrated project INTACT.
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Brummelkamp, T., Fabius, A., Mullenders, J. et al. An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors. Nat Chem Biol 2, 202–206 (2006). https://doi.org/10.1038/nchembio774
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DOI: https://doi.org/10.1038/nchembio774
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