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Cells
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The Role of Mediator Kinase in Cancer...
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The Role of Mediator Kinase in Cancer

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 37579

Special Issue Editor

Dr. Ron Firestein

E-Mail Website
Guest Editor
Head of Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
Interests: cancer; drug discovery; functional genomics; precision medicine; stem cells; epigenetics

Special Issue Information

Dear Colleagues,

CDK8 and its paralog, CDK19, collectively termed ‘Mediator Kinase’, are cyclin-dependent kinases that have been implicated as key rheostats in cellular homeostasis and developmental programming. Mediator facilitates gene expression by bridging promoters with transcription factors bound to cell lineage and cancer- specific enhancers. As such, there is immense interest in developing therapeutic agents that can disrupt Mediator function in a context dependent manner. Recentstudies have shown that pharmacological targeting of CDK8/19 is an attractive strategy for different cancers. Nevertheless, major questions remain regarding the safety of Mediator kinase targeted therapies.  This special issue will address both therapeutic opportunities and challenges of drugging the Mediator kinases.

Dr. Ron Firestein
Guest Editor

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Keywords

  • Chromatin
  • Transcription
  • Cancer genetics
  • Oncogene
  • Signalling
  • Mediator
  • Drug development

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Published Papers (4 papers)

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Research

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17 pages, 3873 KiB  
Article
Systemic Toxicity Reported for CDK8/19 Inhibitors CCT251921 and MSC2530818 Is Not Due to Target Inhibition
by Mengqian Chen, Jing Li, Jiaxin Liang, Zanshé S. Thompson, Katie Kathrein, Eugenia V. Broude and Igor B. Roninson
Cells 2019, 8(11), 1413; https://doi.org/10.3390/cells8111413 - 9 Nov 2019
Cited by 33 | Viewed by 6994
Abstract
CDK8/19 kinases, which mediate transcriptional reprogramming, have become an active target for cancer drug discovery. Several small-molecule CDK8/19 inhibitors showed in vivo efficacy and two have entered clinical trials, with no significant toxicities reported. However, Clarke et al. (eLife 2016; 5; e20722) found [...] Read more.
CDK8/19 kinases, which mediate transcriptional reprogramming, have become an active target for cancer drug discovery. Several small-molecule CDK8/19 inhibitors showed in vivo efficacy and two have entered clinical trials, with no significant toxicities reported. However, Clarke et al. (eLife 2016; 5; e20722) found severe systemic toxicity associated with two potent CDK8/19 inhibitors, Cmpd3 (CCT251921) and Cmpd4 (MSC2530818), and suggested that their toxicity was due to on-target effects. Here, we compared five CDK8/19 inhibitors: Cmpd3, Cmpd4, Senexin B, 16-didehydro-cortistatin A (dCA) and 15w, in different assays. Only Cmpd4 showed striking toxicity in developing zebrafish. In cell-based assays for CDK8 and CDK19 inhibition, Cmpd3, Cmpd4, dCA and 15w showed similar low-nanomolar potency and efficacy against CDK8 and CDK19, while Senexin B was less potent. Only dCA produced sustained inhibition of CDK8/19-dependent gene expression. While toxicity of different compounds did not correlate with their effects on CDK8 and CDK19, kinome profiling identified several off-target kinases for both Cmpd3 and Cmpd4, which could be responsible for their toxicity. Off-target activities could have been achieved in the study of Clarke et al. due to high in vivo doses of Cmpd3 and Cmpd4, chosen for the ability to inhibit STAT1 S727 phosphorylation in tumor xenografts. We show here that STAT1 S727 phosphorylation is induced by various cytokines and stress stimuli in CDK8/19-independent manner, indicating that it is not a reliable pharmacodynamic marker of CDK8/19 activity. These results illustrate the need for careful off-target analysis and dose selection in the development of CDK8/19 inhibitors. Full article
(This article belongs to the Special Issue The Role of Mediator Kinase in Cancer )
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11 pages, 2687 KiB  
Article
Characterizing CDK8/19 Inhibitors through a NFκB-Dependent Cell-Based Assay
by Jing Li, Hao Ji, Donald C. Porter, Eugenia V. Broude, Igor B. Roninson and Mengqian Chen
Cells 2019, 8(10), 1208; https://doi.org/10.3390/cells8101208 - 6 Oct 2019
Cited by 10 | Viewed by 5525
Abstract
Cell-based assays for CDK8/19 inhibition are not easily defined, since there are no known cellular functions unique to these kinases. To solve this problem, we generated derivatives of 293 cells with CRISPR knockout of one or both of CDK8 and CDK19. Double knockout [...] Read more.
Cell-based assays for CDK8/19 inhibition are not easily defined, since there are no known cellular functions unique to these kinases. To solve this problem, we generated derivatives of 293 cells with CRISPR knockout of one or both of CDK8 and CDK19. Double knockout (dKO) of CDK8 and CDK19 together (but not individually) decreased the induction of transcription by NFκB (a CDK8/19-potentiated transcription factor) and abrogated the effect of CDK8/19 inhibitors on such induction. We generated wild type (WT) and dKO cell lines expressing luciferase from an NFκB-dependent promoter. Inhibitors selective for CDK8/19 over other CDKs decreased TNFα-induced luciferase expression in WT cells by ~80% with no effect on luciferase induction in dKO cells. In contrast, non-selective CDK inhibitors flavopiridol and dinaciclib and a CDK7/12/13 inhibitor THZ1 (but not CDK4/6 inhibitor palbociclib) suppressed luciferase induction in both WT and dKO cells, indicating a distinct role for other CDKs in the NFκB pathway. We used this assay to characterize a series of thienopyridines with in vitro bone anabolic activity, one of which was identified as a selective CDK8/19 inhibitor. Thienopyridines inhibited luciferase induction in the WT but not dKO cells and their IC50 values in the WT reporter assay showed near-perfect correlation (R2 = 0.98) with their reported activities in a bone anabolic activity assay, confirming that the latter function is mediated by CDK8/19 and validating our assay as a robust and quantitative method for CDK8/19 inhibition. Full article
(This article belongs to the Special Issue The Role of Mediator Kinase in Cancer )
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16 pages, 4657 KiB  
Article
Identifying Cancers Impacted by CDK8/19
by Igor B. Roninson, Balázs Győrffy, Zachary T. Mack, Alexander A. Shtil, Michael S. Shtutman, Mengqian Chen and Eugenia V. Broude
Cells 2019, 8(8), 821; https://doi.org/10.3390/cells8080821 - 3 Aug 2019
Cited by 40 | Viewed by 7327
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Role of Mediator Kinase in Cancer )
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Review

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29 pages, 2653 KiB  
Review
Transcriptional Regulation of Wnt/β-Catenin Pathway in Colorectal Cancer
by Jia Bian, Marius Dannappel, Chunhua Wan and Ron Firestein
Cells 2020, 9(9), 2125; https://doi.org/10.3390/cells9092125 - 19 Sep 2020
Cited by 179 | Viewed by 17127
Abstract
The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated diseases and cancers, especially as a key driver in the initiation and progression of colorectal cancer (CRC). Loss or inactivation of Adenomatous [...] Read more.
The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated diseases and cancers, especially as a key driver in the initiation and progression of colorectal cancer (CRC). Loss or inactivation of Adenomatous polyposis coli (APC) results in constitutive activation of Wnt/β-catenin signaling, which is considered as an initiating event in the development of CRC. Increased Wnt/β-catenin signaling is observed in virtually all CRC patients, underscoring the importance of this pathway for therapeutic intervention. Prior studies have deciphered the regulatory networks required for the cytoplasmic stabilisation or degradation of the Wnt pathway effector, β-catenin. However, the mechanism whereby nuclear β-catenin drives or inhibits expression of Wnt target genes is more diverse and less well characterised. Here, we describe a brief synopsis of the core canonical Wnt pathway components, set the spotlight on nuclear mediators and highlight the emerging role of chromatin regulators as modulators of β-catenin-dependent transcription activity and oncogenic output. Full article
(This article belongs to the Special Issue The Role of Mediator Kinase in Cancer )
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