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Τρίτη 10 Οκτωβρίου 2017

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

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Sampada Kalan, Ramon Amat, Miriam Merzel Schachter, Nicholas Kwiatkowski, Brian J. Abraham, Yanke Liang, Tinghu Zhang, Calla M. Olson, Stéphane Larochelle, Richard A. Young, Nathanael S. Gray, Robert P. Fisher
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.

Graphical abstract

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Teaser

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.


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