Triple-negative breast cancers are dependent on expression of CDK7 and its transcriptional targets.

  • Major finding: Triple-negative breast cancers are dependent on expression of CDK7 and its transcriptional targets.

  • Concept: TNBC requires CDK7 for expression of an “Achilles cluster” of genes essential for growth and survival.

  • Impact: TNBCs are sensitive to pharmacologic inhibition of CDK7, a promising avenue for new therapy.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective treatment options and is characterized by a high degree of genetic heterogeneity compared with estrogen receptor/progesterone receptor–positive (ER/PR+) breast cancer. Despite this heterogeneity, TNBCs share a characteristic gene expression program, which may make them sensitive to pharmacologic transcription inhibitors. To test this hypothesis, Wang, Zhang, Kwiatkowski, and colleagues treated breast cancer cell lines and patient-derived xenografts with THZ1, a specific covalent inhibitor of cyclin-dependent kinase 7 (CDK7), and THZ2, an analogue with improved pharmacokinetics. Compared with ER/PR+ tumors, TNBCs were exquisitely and uniquely sensitive to CDK7 inhibition. THZ1 treatment induced apoptosis in TNBC cells, but did not alter the cell cycle, suggesting that the effect of CDK7 inhibition is not due to its role in regulating cell-cycle–related CDKs. The dependence of TNBC cells on CDK7 was further confirmed using CRISPR/Cas9–mediated deletion of CDK7, which reduced cell growth and induced apoptosis in TNBC, but not ER/PR+, breast cancer cells. Analysis of TNBC and ER/PR+ cell lines treated with THZ1 identified a set of genes that were overexpressed in TNBC cells compared with ER/PR+ cells and were sensitive to THZ1 treatment. These genes, including EGFR, MYC, and SOX9, represented a TNBC-specific “Achilles cluster” of genes involved in signaling and transcriptional regulation that is critical for the growth and survival of TNBC cells. Furthermore, these genes were found to be preferentially associated with super-enhancers in TNBC cells, which may make them especially sensitive to THZ1. Taken together, these finding suggest that CDK7 inhibition may be a promising therapy for TNBC, as it inhibits multiple genes essential for the survival of TNBC cells.

Wang Y, Zhang T, Kwiatkowski N, Abraham BJ, Lee TI, Xie S, et al. CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell 2015;163:174–86.