Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors
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 d...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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Elsevier
2018
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| Online Access: | http://hdl.handle.net/1721.1/117058 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1826205275918434304 |
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| author | Kalan, Sampada Amat, Ramon Schachter, Miriam Merzel Kwiatkowski, Nicholas Abraham, Brian J. Liang, Yanke Zhang, Tinghu Olson, Calla M. Larochelle, Stéphane Gray, Nathanael S. Fisher, Robert P. Young, Richard A. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Kalan, Sampada Amat, Ramon Schachter, Miriam Merzel Kwiatkowski, Nicholas Abraham, Brian J. Liang, Yanke Zhang, Tinghu Olson, Calla M. Larochelle, Stéphane Gray, Nathanael S. Fisher, Robert P. Young, Richard A. |
| author_sort | Kalan, Sampada |
| collection | MIT |
| description | 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 Cdk7asinhibitor 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 CDK7asmutation 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. 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. Keywords: Cdk7; p53; colon cancer; synthetic lethality; transcription; 5-fluorouracil; nutlin-3; apoptosis; chemical genetics; CDK inhibitor |
| first_indexed | 2024-09-23T13:10:08Z |
| format | Article |
| id | mit-1721.1/117058 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:10:08Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1170582022-10-01T13:29:49Z Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors Kalan, Sampada Amat, Ramon Schachter, Miriam Merzel Kwiatkowski, Nicholas Abraham, Brian J. Liang, Yanke Zhang, Tinghu Olson, Calla M. Larochelle, Stéphane Gray, Nathanael S. Fisher, Robert P. Young, Richard A. Massachusetts Institute of Technology. Department of Biology Young, Richard A 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 Cdk7asinhibitor 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 CDK7asmutation 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. 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. Keywords: Cdk7; p53; colon cancer; synthetic lethality; transcription; 5-fluorouracil; nutlin-3; apoptosis; chemical genetics; CDK inhibitor National Institutes of Health (U.S.) (Grant HG002668) 2018-07-23T19:47:26Z 2018-07-23T19:47:26Z 2017-10 2017-08 2018-07-13T17:24:52Z Article http://purl.org/eprint/type/JournalArticle 2211-1247 http://hdl.handle.net/1721.1/117058 Kalan, Sampada et al. “Activation of the P53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors.” Cell Reports 21, 2 (October 2017): 467–481 © 2017 The Author(s) https://orcid.org/0000-0001-8855-8647 http://dx.doi.org/10.1016/J.CELREP.2017.09.056 Cell Reports Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Kalan, Sampada Amat, Ramon Schachter, Miriam Merzel Kwiatkowski, Nicholas Abraham, Brian J. Liang, Yanke Zhang, Tinghu Olson, Calla M. Larochelle, Stéphane Gray, Nathanael S. Fisher, Robert P. Young, Richard A. Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors |
| title | Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors |
| title_full | Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors |
| title_fullStr | Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors |
| title_full_unstemmed | Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors |
| title_short | Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors |
| title_sort | activation of the p53 transcriptional program sensitizes cancer cells to cdk7 inhibitors |
| url | http://hdl.handle.net/1721.1/117058 https://orcid.org/0000-0001-8855-8647 |
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