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

ABSTRACT: 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-tr

SUBMITTER: Kalan S 

PROVIDER: S-EPMC5687273 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature