期刊
NATURE CHEMICAL BIOLOGY
卷 12, 期 1, 页码 22-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1965
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资金
- 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
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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