Identifying Cancers Impacted by CDK8/19

Igor B Roninson1,2, Balázs Győrffy3,4, Zachary T Mack1

  • 1Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.

Cells
|August 7, 2019
PubMed

Insights

CDK8 and CDK19 inhibitors show promise in treating cancers driven by transcriptional changes. These Mediator kinases are frequently altered in aggressive prostate cancers and other malignancies, suggesting broader therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cyclin-dependent kinase (CDK) 8 and CDK19 are Mediator complex kinases involved in transcriptional regulation.
  • These kinases are implicated in the pathogenesis of various cancers.
  • CDK8/19 inhibitors are entering clinical trials for breast cancer and acute myeloid leukemia (AML).

Purpose of the Study:

  • To identify additional cancer types that may benefit from CDK8/19 inhibitor therapy.
  • To investigate the role of CDK8, CDK19, and CCNC in different tumor types.

Main Methods:

  • Querying genomic and transcriptomic databases.
  • sgRNA screening of tumor cell lines.
  • Analysis of clinical samples for gene alterations and survival correlations.

Main Results:

  • CDK8/19 dependency was observed in most tumor types, excluding some central nervous system tumors.
  • High-frequency gene amplification of CDK8/19/CCNC was found in aggressive prostate cancers, GI tract, breast, bladder, and sarcoma.
  • CDK8 expression correlated with poorer survival in breast, prostate, cervical cancers, and esophageal adenocarcinoma, particularly in tumors with low mutation burden.

Conclusions:

  • Mediator kinases are crucial in cancers driven by transcriptional alterations rather than solely mutational changes.
  • These findings support further investigation of CDK8/19 inhibitors in a wider range of cancer types.

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