Abstract
CDK8 and CDK19 Mediator kinases are transcriptional co-regulators implicated in several types of cancer. Small-molecule CDK8/19 inhibitors have recently entered or are entering clinical trials, starting with breast cancer and acute myeloid leukemia (AML). To identify other cancers where these novel drugs may provide benefit, we queried genomic and transcriptomic databases for potential impact of CDK8, CDK19, or their binding partner CCNC. sgRNA analysis of a panel of tumor cell lines showed that most tumor types represented in the panel, except for some central nervous system tumors, were not dependent on these genes. In contrast, analysis of clinical samples for alterations in these genes revealed a high frequency of gene amplification in two highly aggressive subtypes of prostate cancer and in some cancers of the GI tract, breast, bladder, and sarcomas. Analysis of survival correlations identified a group of cancers where CDK8 expression correlated with shorter survival (notably breast, prostate, cervical cancers, and esophageal adenocarcinoma). In some cancers (AML, melanoma, ovarian, and others), such correlations were limited to samples with a below-median tumor mutation burden. These results suggest that Mediator kinases are especially important in cancers that are driven primarily by transcriptional rather than mutational changes and warrant an investigation of their role in additional cancer types.
Highlights
IntroductionA number of small-molecule CDK8/19 inhibitors have been developed [13]
The Mediator kinase CDK8 and its paralog CDK19, together with their binding partner CyclinC (CCNC), have been implicated through experimental studies in several malignancies, including cancers of the colon [1,2,3], breast [4,5,6,7], prostate [8], pancreas [9], melanoma [10], and leukemias [11,12].A number of small-molecule CDK8/19 inhibitors have been developed [13]
As a notable recent example, this approach was used to identify estrogen receptor (ER)-positive breast cancer as a target disease for the inhibitors of CDK4/6 kinases essential for cell cycle progression in G1 [23]
Summary
A number of small-molecule CDK8/19 inhibitors have been developed [13] Such inhibitors showed potentially beneficial effects on leukemia cell proliferation [11,12], tumor invasion [9,14], metastasis [3], or tumor response to other anti-cancer drugs [4,6]. These effects of CDK8/19 inhibitors have been demonstrated in several in vivo models, including lung [4], breast [6], colon [3], prostate cancers [15], and leukemia [11]. It is becoming imperative to identify other types of cancer and categories of patients who could benefit from this new class of drugs
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