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

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.

5-fluorouracil; CDK inhibitor; Cdk7; apoptosis; chemical genetics; colon cancer; nutlin-3; p53; synthetic lethality; transcription.