Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors
- Cell Rep. 2017 Oct 10;21(2):467-481. doi: 10.1016/j.celrep.2017.09.056.
- 1. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
- 2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
- 3. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
- 4. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, MA 02142, USA.
- 5. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].
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.