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CRISPR-Cas9-based target validation for p53-reactivating model compounds

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Savai,  Rajkumar
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Wanzel, I., Vischedyk, J. B., Gittler, M. P., Gremke, N., Seiz, J. R., Hefter, M., et al. (2016). CRISPR-Cas9-based target validation for p53-reactivating model compounds. NATURE CHEMICAL BIOLOGY, 12(1), 22-+. doi:10.1038/NCHEMBIO.1965.


Cite as: http://hdl.handle.net/21.11116/0000-0001-BEF0-A
Abstract
Inactivation of the p53 tumor suppressor by Mdm2 is one of the most frequent events in cancer, so compounds targeting the p53-Mdm2 interaction are promising for cancer therapy. Mechanisms conferring resistance to p53-reactivating compounds are largely unknown. Here we show using CRISPR-Cas9-based target validation in lung and colorectal cancer that the activity of nutlin, which blocks the p53-binding pocket of Mdm2, strictly depends on functional p53. In contrast, sensitivity to the drug RITA, which binds the Mdm2-interacting N terminus of p53, correlates with induction of DNA damage. Cells with primary or acquired RITA resistance display cross-resistance to DNA crosslinking compounds such as cisplatin and show increased DNA cross-link repair. Inhibition of FancD2 by RNA interference or pharmacological mTOR inhibitors restores RITA sensitivity. The therapeutic response to p53-reactivating compounds is therefore limited by compound-specific resistance mechanisms that can be resolved by CRISPR-Cas9-based target validation and should be considered when allocating patients to p53-reactivating treatments.