Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2017-10, Vol.21 (2), p.467-481

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.