Preclinical efficacy and molecular mechanism of targeting CDK7-dependent transcriptional addiction in ovarian cancer

Z Zhang, H Peng, X Wang, X Yin, P Ma, Y Jing… - Molecular cancer …, 2017 - AACR
Z Zhang, H Peng, X Wang, X Yin, P Ma, Y Jing, MC Cai, J Liu, M Zhang, S Zhang, K Shi…
Molecular cancer therapeutics, 2017AACR
Ovarian cancer remains a significant cause of gynecologic cancer mortality, and novel
therapeutic strategies are urgently needed in clinic as new treatment options. We previously
showed that BET bromodomain inhibitors displayed promising efficacy for the treatment of
epithelial ovarian cancer by downregulating pivot transcription factors. However, the
potential antitumor activities and molecular mechanisms of other epigenetic or
transcriptional therapies have not been systematically determined. Here, by performing an …
Abstract
Ovarian cancer remains a significant cause of gynecologic cancer mortality, and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential antitumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identified THZ1, a recently developed covalent CDK7 inhibitor, as a new transcription-targeting compound that exerted broad cytotoxicity against ovarian tumors. Mechanistically, CDK7 represented a previously unappreciated actionable vulnerability in ovarian cancer, and CDK7 inhibition led to a pronounced dysregulation of gene transcription, with a preferential repression of E2F-regulated genes and transcripts associated with super-enhancers. Our findings revealed the molecular underpinnings of THZ1 potency and established pharmaceutically targeting transcriptional addiction as a promising therapeutic strategy in aggressive ovarian cancer. Mol Cancer Ther; 16(9); 1739–50. ©2017 AACR.
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