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Published on: May 21, 2019
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.
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.
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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