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

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.

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Genre: Journal Article

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 Creators:
Wanzel, Ichael, Author
Vischedyk, Jonas B., Author
Gittler, Miriam P., Author
Gremke, Niklas, Author
Seiz, Julia R., Author
Hefter, Mirjam, Author
Noack, Magdalena, Author
Savai, Rajkumar1, Author              
Mernberger, Marco, Author
Charles, Joel P., Author
Schneikert, Jean, Author
Bretz, Anne Catherine, Author
Nist, Andrea, Author
Stiewe, Thorsten, Author
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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Free keywords: SMALL-MOLECULE RITA; DOUBLE-STRAND BREAKS; IN-VIVO; CANCER-CELLS; P53 RESTORATION; FANCD2 MONOUBIQUITINATION; ANTAGONIST NUTLIN-3; DNA-DAMAGE; MUTANT P53; PATHWAYBiochemistry & Molecular Biology;
 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.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000366674400007
DOI: 10.1038/NCHEMBIO.1965
 Degree: -

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Title: NATURE CHEMICAL BIOLOGY
Source Genre: Journal
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Publ. Info: 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA : NATURE PUBLISHING GROUP
Pages: - Volume / Issue: 12 (1) Sequence Number: - Start / End Page: 22 - + Identifier: ISSN: 1552-4450