CDK8: a new breast cancer target

Close to 70% of all breast cancers express the estrogen receptor (ER), one of the oldest molecular targets in oncology. Once ER is bound to estrogen in the cytoplasm, it enters the nucleus where it binds to specific DNA sequences (estrogen response elements) in or near the promoters of a limited set of genes, inducing their transcription. ER-mediated transcription produces a mitogenic effect in ER-positive breast cancer cells. Agents interfering with ER signaling have long been used for hormone therapy of ER-positive breast cancers. These drugs include aromatase inhibitors that inhibit estrogen synthesis and selective estrogen receptor degraders (SERDs), which both block estrogen interaction with ER and cause ER degradation. In addition, selective estrogen receptor modifiers (SERMs, most notably tamoxifen) not only compete with estrogen for ER binding but also subvert the function of ER, changing its transcription-regulating activity in a way that suppresses rather than promotes the growth of breast cancers. While generally very efficient in an adjuvant setting, hormone therapy of metastatic breast cancer patients frequently fails, as their tumors modify their ER, making it less dependent on estrogen, or start utilizing other signal transduction pathways to replace ER. A recent article by McDermott et al. [1] from the laboratory of Eugenia Broude at the University of South Carolina suggests that a new class of experimental drugs targeting a transcriptional regulator CDK8 may have a positive impact on the challenges facing hormone therapy of ER-positive breast cancer. CDK8 and its " twin " CDK19 belong to the same cyclin-dependent kinase (CDK) family as CDK4/6, the target of effective drugs that have recently entered the clinical armamentarium for ER-positive breast cancers. In contrast to CDK4/6, CDK8 does not mediate cell cycle progression and CDK8 inhibitors do not generally affect cell proliferation [2]. Instead, CDK8 acts as a co-regulator of transcription that cooperates with several transcription factors, in most cases enhancing the activity of these factors [3, 4]. CDK8 was found to be upregulated in breast cancers and associated with tumor progression; elevated expression of CDK8 and its interactive proteins has been linked to shorter relapse-free survival of breast cancer patients [2, 5, 6]. McDermott et al. [1] now found that CDK8 expression in breast cancers is inversely associated with the expression of ER, a finding that made them investigate if CDK8 could affect ER signaling. They showed that CDK8 inhibition, either with small-molecule CDK8 inhibitors (Senexin A and Senexin …