Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors

作者：Kalan Sampada; Amat Ramon; Schachter Miriam Merzel; Kwiatkowski Nicholas; Abraham Brian J; Liang Yanke; Zhang Tinghu; Olson Calla M; Larochelle Stephane; Young Richard A; Gray Nathanael S; Fisher Robert P^*

来源：Cell Reports, 2017, 21(2): 467-481.

DOI：10.1016/j.celrep.2017.09.056

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.

• 出版日期2017-10-10
• 单位MIT