Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13
- Dana-Farber Cancer Institute, United States
- Baylor College of Medicine, United States
Abstract
High-grade serous ovarian cancer is characterized by extensive copy number alterations, among which the amplification of MYC oncogene occurs in nearly half of tumors. We demonstrate that ovarian cancer cells highly depend on MYC for maintaining their oncogenic growth, indicating MYC as a therapeutic target for this difficult-to-treat malignancy. However, targeting MYC directly has proven difficult. We screen small molecules targeting transcriptional and epigenetic regulation, and find that THZ1 - a chemical inhibiting CDK7, CDK12, and CDK13 - markedly downregulates MYC. Notably, abolishing MYC expression cannot be achieved by targeting CDK7 alone, but require the combined inhibition of CDK7, CDK12, and CDK13. In 11 patient derived xenografts models derived from heavily pre-treated ovarian cancer patients, administration of THZ1 induces significant tumor growth inhibition with concurrent abrogation of MYC expression. Our study indicates that targeting these transcriptional CDKs with agents such as THZ1 may be an effective approach for MYC-dependent ovarian malignancies.
Data availability
RNA sequencing data have been deposited in GEO under accession code GSE116282.
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RNA sequencing data fromGene Expression Omnibus, GSE116282.
Article and author information
Author details
Funding
National Cancer Institute (NIH R01 CA197336-02)
- Nathanael S Gray
National Cancer Institute (NIH R01 CA179483-02)
- Nathanael S Gray
U.S. Department of Defense (W81XWH-14-OCRP-OCACAOC140632 award)
- Panagiotis A Konstantinopoulos
Cancer Prevention Research Institute of Texas (RR150093)
- Charles Y Lin
National Cancer Institute (R01CA215452-01)
- Charles Y Lin
American Cancer Society (Postdoctoral Fellowship PF-17-010-01-CDD)
- Behnam Nabet
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ross L Levine, Memorial Sloan Kettering Cancer Center, United States
Ethics
Animal experimentation: All animal experiments were conducted in accordance with the animal use guidelines from the NIH and with protocols (Protocol # 11-044) approved by the Dana-Farber Cancer Institute Animal Care and Use Committee. Full details are described in Materials and Methods - Animal Studies.
Version history
- Received: June 8, 2018
- Accepted: November 11, 2018
- Accepted Manuscript published: November 13, 2018 (version 1)
- Version of Record published: November 23, 2018 (version 2)
Copyright
© 2018, Zeng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13
eLife 7:e39030.
https://doi.org/10.7554/eLife.39030
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