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Identifying Cancers Impacted by CDK8/19

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...

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Autores principales: Roninson, Igor B., Győrffy, Balázs, Mack, Zachary T., Shtil, Alexander A., Shtutman, Michael S., Chen, Mengqian, Broude, Eugenia V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721656/
https://www.ncbi.nlm.nih.gov/pubmed/31382571
http://dx.doi.org/10.3390/cells8080821
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author Roninson, Igor B.
Győrffy, Balázs
Mack, Zachary T.
Shtil, Alexander A.
Shtutman, Michael S.
Chen, Mengqian
Broude, Eugenia V.
author_facet Roninson, Igor B.
Győrffy, Balázs
Mack, Zachary T.
Shtil, Alexander A.
Shtutman, Michael S.
Chen, Mengqian
Broude, Eugenia V.
author_sort Roninson, Igor B.
collection PubMed
description 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.
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spelling pubmed-67216562019-09-10 Identifying Cancers Impacted by CDK8/19 Roninson, Igor B. Győrffy, Balázs Mack, Zachary T. Shtil, Alexander A. Shtutman, Michael S. Chen, Mengqian Broude, Eugenia V. Cells Article 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. MDPI 2019-08-03 /pmc/articles/PMC6721656/ /pubmed/31382571 http://dx.doi.org/10.3390/cells8080821 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Roninson, Igor B.
Győrffy, Balázs
Mack, Zachary T.
Shtil, Alexander A.
Shtutman, Michael S.
Chen, Mengqian
Broude, Eugenia V.
Identifying Cancers Impacted by CDK8/19
title Identifying Cancers Impacted by CDK8/19
title_full Identifying Cancers Impacted by CDK8/19
title_fullStr Identifying Cancers Impacted by CDK8/19
title_full_unstemmed Identifying Cancers Impacted by CDK8/19
title_short Identifying Cancers Impacted by CDK8/19
title_sort identifying cancers impacted by cdk8/19
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721656/
https://www.ncbi.nlm.nih.gov/pubmed/31382571
http://dx.doi.org/10.3390/cells8080821
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