2. Academic Validation
  3. Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13

Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13

  • Elife. 2018 Nov 13;7:e39030. doi: 10.7554/eLife.39030.
Mei Zeng 1 2,  Nicholas P Kwiatkowski 1 2,  Tinghu Zhang 1 2,  Behnam Nabet 1 2,  Mousheng Xu 1 3,  Yanke Liang 1 2,  Chunshan Quan 1 2,  Jinhua Wang 1 2,  Mingfeng Hao 1 2,  Sangeetha Palakurthi 4,  Shan Zhou 4,  Qing Zeng 4,  Paul T Kirschmeier 4,  Khyati Meghani 5,  Alan L Leggett 1 2,  Jun Qi 1 3,  Geoffrey I Shapiro 6,  Joyce F Liu 7,  Ursula A Matulonis 7,  Charles Y Lin 8 9,  Panagiotis A Konstantinopoulos 7,  Nathanael S Gray 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
  • 3 Department of Medicine, Harvard Medical School, Boston, United States.
  • 4 Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, United States.
  • 5 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States.
  • 6 Early Drug Development Center, Dana-Farber Cancer Institute, Boston, United States.
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
  • 8 Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
  • 9 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
PMID: 30422115 DOI: 10.7554/eLife.39030
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 requires 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.

Keywords

CDK12/13; CDK7; MCL-1; MYC; THZ1; cancer biology; human; mouse; ovarian cancer.

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