Editors' ChoiceCancer

Inhibiting one kinase to kill them all

Sci. Signal.  06 Oct 2015:
Vol. 8, Issue 397, pp. ec284
DOI: 10.1126/scisignal.aad5688

Triple-negative breast cancer (TNBC) has a characteristic gene signature but lacks a common genetic alteration that drives the cancer, thus finding a common therapeutic is challenging. Cyclin-dependent kinase 7 (CDK7), which promotes transcription as well as the cell cycle, is critical for the survival of neuroblastoma, lung cancer, and leukemia cells that are driven by the transcription factor MYCN. Wang et al. found that TNBC are commonly, and among breast cancers uniquely, dependent on the transcription-regulating function of CDK7. RNA interference, CRISPR/Cas9-mediated gene editing or pharmacological inhibition of CDK7 suppressed proliferation and induced apoptotic cell death in TNBC cells (but not hormone receptor–positive breast cancer cells), both in culture and in cell line– or patient-derived xenografts in mice. However, the CDK7 inhibitor did not disrupt cell cycle progression. Microarray and gene ontology analysis of cell lines and primary cells representing TNBC and hormone receptor–positive cancer cells revealed that the TNBC-specific genes that were particularly sensitive to CDK7 inhibition were enriched for those encoding signaling molecules and transcription factors. A subset of the CDK7-sensitive TNBC-specific genes was enriched in those that are associated with DNA sequences called super-enhancers, which concentrate transcriptional complexes to increase gene expression. Among these that associate with super-enhancers, gene editing–mediated ablation of the transcription factors SOX9, MYC, FOSL1, or FOXC1 suppressed proliferation and induced apoptosis selectively in TNBC cells but not hormone receptor–positive cancer cells. The findings indicate that CDK7 promotes the transcription of critical genes in TNBC and that CDK7 inhibitors could be effective in treating patients with TNBC.

Y. Wang, T. Zhang, N. Kwiatkowski, B. J. Abraham, T. I. Lee, S. Xie, H. Yuzugullu, T. Von, H. Li, Z. Lin, D. G. Stover, E. Lim, Z. C. Wang, J. D. Iglehart, R. A. Young, N. S. Gray, J. J. Zhao, CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell 163, 174–186 (2015). [PubMed]