Cell Reports
Volume 21, Issue 2, 10 October 2017, Pages 467-481
Journal home page for Cell Reports

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

https://doi.org/10.1016/j.celrep.2017.09.056Get rights and content
Under a Creative Commons license
open access

Highlights

  • Cdk7 inhibition plus p53 activation cause synthetic lethality in cancer cells

  • Chemical genetics lead to the discovery of synthetic-lethal drug combinations

  • Synergy with p53 activators is enhanced by increasing selectivity of the Cdk7 inhibitor

  • Cdk7 inhibition modulates p53 transcriptional program to favor pro-apoptotic targets

Summary

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 Cdk7as 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 CDK7as 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.

Keywords

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

Cited by (0)

6

These authors contributed equally

7

Lead Contact