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

• Published in: Cell reports (Cambridge) Vol. 21; no. 2; pp. 467 - 481
• Main Authors: Kalan, Sampada, Amat, Ramon, Schachter, Miriam Merzel, Kwiatkowski, Nicholas, Abraham, Brian J., Liang, Yanke, Zhang, Tinghu, Olson, Calla M., Larochelle, Stéphane, Young, Richard A., Gray, Nathanael S., Fisher, Robert P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2017; Elsevier
• Subjects: 5-fluorouracil; apoptosis; CDK inhibitor; Cdk7; chemical genetics; colon cancer; nutlin-3; p53; synthetic lethality; transcription; 5-fluorouracil; Cdk7; CDK inhibitor; transcription; nutlin-3; chemical genetics; colon cancer; synthetic lethality; apoptosis; p53
• ISSN: 2211-1247; 2211-1247
• 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 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. [Display omitted] •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 Kalan et al. find that activation of the p53 tumor suppressor protein in human colon cancer-derived cells can induce transcriptional dependency on Cdk7, analogous to constitutive dependencies described in other tumors driven by oncogenic transcription factors. This work provides a proof of concept for combining p53-activating agents with Cdk7 inhibitors to elicit synthetic lethality.