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

• Main Authors: Mei Zeng, Nicholas P Kwiatkowski, Tinghu Zhang, Behnam Nabet, Mousheng Xu, Yanke Liang, Chunshan Quan, Jinhua Wang, Mingfeng Hao, Sangeetha Palakurthi, Shan Zhou, Qing Zeng, Paul T Kirschmeier, Khyati Meghani, Alan L Leggett, Jun Qi, Geoffrey I Shapiro, Joyce F Liu, Ursula A Matulonis, Charles Y Lin, Panagiotis A Konstantinopoulos, Nathanael S Gray
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2018-11-01
• Series: eLife
• Subjects: ovarian cancer; MYC; THZ1; CDK7; CDK12/13; MCL-1
• Online Access: https://elifesciences.org/articles/39030

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.