Journal
NATURE CHEMICAL BIOLOGY
Volume 12, Issue 1, Pages 22-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1965
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Funding
- Deutsche Forschungsgemeinschaft grants [WA 2725/1-1, TRR81, STI 182/3-2, STI 182/7-1]
- European Research Council grant [P73CANCER 260431]
- Deutsche Krebshilfe grant [111250]
- Deutsche Jose Carreras Leukamie-Stiftung grant
- Von-Behring-Rontgen-Stiftung grant
- Rhon Klinikum AG grant
- LOEWE Universities of Giessen and Marburg Lung Center grant
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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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