CDK7-Dependent Transcriptional Addiction in Triple-Negative Breast Cancer

• Main Authors: Wang, Yubao (Author), Zhang, Tinghu (Author), Kwiatkowski, Nicholas (Author), Abraham, Brian J (Author), Lee, Tong Ihn (Author), Xie, Shaozhen (Author), Yuzugullu, Haluk (Author), Von, Thanh (Author), Li, Heyuan (Author), Lin, Ziao (Author), Stover, Daniel G (Author), Lim, Elgene (Author), Wang, Zhigang C (Author), Iglehart, J. Dirk (Author), Gray, Nathanael S (Author), Zhao, Jean J (Author), Young, Richard A. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Young, Richard A (Contributor)
• Format: Article
• Language: English
• Published: Elsevier B.V., 2017-03-27T20:03:34Z.
• Subjects: Article
• Online Access: Get fulltext

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing kinase inhibitors and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not hormone receptor-positive breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An "Achilles cluster" of TNBC-specific genes is especially sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be a useful therapy for this challenging cancer.
National Institutes of Health (U.S.) (NIH/NCI P50 CA168504)
Dana-Farber Cancer Institute (MIT-DFCI Bridge grant)
National Institutes of Health (U.S.) (NIH R01CA179483-01)