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.

The following data sets were generated

Article and author information

Author details

  1. Mei Zeng

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  2. Nicholas P Kwiatkowski

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Nicholas P Kwiatkowski, is an inventor on a patent application covering THZ1 (patent application number WO/2014/063068 A1), which is licensed to Syros Pharmaceuticals.
  3. Tinghu Zhang

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Tinghu Zhang, is an inventor on a patent application covering THZ1 (patent application number WO/2014/063068 A1), which is licensed to Syros Pharmaceuticals.
  4. Behnam Nabet

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6738-4200
  5. Mousheng Xu

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  6. Yanke Liang

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  7. Chunshan Quan

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  8. Jinhua Wang

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  9. Mingfeng Hao

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  10. Sangeetha Palakurthi

    Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Shan Zhou

    Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  12. Qing Zeng

    Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  13. Paul T Kirschmeier

    Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  14. Khyati Meghani

    Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  15. Alan L Leggett

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  16. Jun Qi

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  17. Geoffrey I Shapiro

    Early Drug Development Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  18. Joyce F Liu

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  19. Ursula A Matulonis

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  20. Charles Y Lin

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    For correspondence
    Charles.Y.Lin@bcm.edu
    Competing interests
    Charles Y Lin, is a consultant of Jnana Therapeutics and is a shareholder and inventor of IP licensed to Syros Pharmaceuticals.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9155-090X
  21. Panagiotis A Konstantinopoulos

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    Panagiotis_Konstantinopoulos@DFCI.HARVARD.EDU
    Competing interests
    No competing interests declared.
  22. Nathanael S Gray

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    nathanael_gray@dfci.harvard.edu
    Competing interests
    Nathanael S Gray, is an inventor on a patent application covering THZ1 (patent application number WO/2014/063068 A1), which is licensed to Syros Pharmaceuticals.Is a scientific founder and equity holder of Syros Pharmaceuticals, C4 Therapeutics, Petra Pharma, Gatekeeper Pharmaceuticals, and Soltego.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5354-7403

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.

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.

Reviewing Editor

  1. Ross L Levine, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: June 8, 2018
  2. Accepted: November 11, 2018
  3. Accepted Manuscript published: November 13, 2018 (version 1)
  4. 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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  1. Mei Zeng
  2. Nicholas P Kwiatkowski
  3. Tinghu Zhang
  4. Behnam Nabet
  5. Mousheng Xu
  6. Yanke Liang
  7. Chunshan Quan
  8. Jinhua Wang
  9. Mingfeng Hao
  10. Sangeetha Palakurthi
  11. Shan Zhou
  12. Qing Zeng
  13. Paul T Kirschmeier
  14. Khyati Meghani
  15. Alan L Leggett
  16. Jun Qi
  17. Geoffrey I Shapiro
  18. Joyce F Liu
  19. Ursula A Matulonis
  20. Charles Y Lin
  21. Panagiotis A Konstantinopoulos
  22. Nathanael S Gray
(2018)
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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    Sarcomas comprise approximately 1% of all human malignancies; treatment resistance is one of the major reasons for the poor prognosis of sarcomas. Accumulating evidence suggests that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs, and circular RNAs, are important molecules involved in the crosstalk between resistance to chemotherapy, targeted therapy, and radiotherapy via various pathways.

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    Observational studies revealed the ectopic expression of ncRNAs in sarcoma patients who had different responses to antitumor treatments. Experimental studies have confirmed crosstalk between cellular pathways pertinent to chemotherapy, targeted therapy, and radiotherapy resistance. Of the included studies, W-MeQS scores ranged from 3 to 10 (average score = 5.42). Of the 12 articles that investigated ncRNAs as biomarkers, none included a validation cohort. Selective reporting of the sensitivity, specificity, and receiver operating curves was common.

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    Funding:

    This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).