期刊
CELL REPORTS
卷 21, 期 2, 页码 467-481出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.056
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资金
- Beatriu de Pinos fellowship of the Generalitat de Catalunya [2010 BP-A 00430]
- NIH [T32 CA78207, GM105773, GM104291, CA179483, HG002668]
- Bridge Project
- Koch Institute for Integrative Cancer Research at MIT
- DanaFarber/Harvard Cancer Center
- NIH (NCI) [P30 CA196521]
Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer-derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here, we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7(as) inhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1, or the more selective YKL-1-116. The effects were allele specific; a CDK7(as) mutation conferred both sensitivity to bulky adenine analogs and resistance to covalent inhibitors. Non-transformed colon epithelial cells were resistant to these combinations, as were cancer-derived cells with p53-inactivating mutations. Apoptosis was dependent on death receptor DR5, a p53 transcriptional target whose expression was refractory to Cdk7 inhibition. Therefore, p53 activation induces transcriptional dependency to sensitize cancer cells to Cdk7 inhibition.
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