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| Status |
Public on Oct 10, 2017 |
| Title |
Activation of the p53 transcriptional program sensitizes cancer cells to Cdk7 inhibitors |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| 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.
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| Overall design |
RNAseq in colorectal cancer cell line HCT116 in the presence or absence of CDK7 and p53 inhibitors
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| Contributor(s) |
Kalan S, Amat R, Shachter MM, Kwiatkowski N, Abraham BJ, Liang Y, Zhang T, M.Olson C, Larochelle S, Young RA, Gray NS, Fisher RP |
| Citation(s) |
29020632 |
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| Submission date |
Jun 07, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Richard A Young |
| E-mail(s) |
young_computation@wi.mit.edu
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| Phone |
617-258-5219
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| Organization name |
Whitehead Institute for Biomedical Research
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| Lab |
Young Lab
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| Street address |
9 Cambridge Center
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA389616 |
| SRA |
SRP108803 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE99794_RAW.tar |
5.8 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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