CDK19 is a Regulator of Triple-Negative Breast Cancer Growth
Open accessAbstract
Triple-negative breast cancer (TNBC) is a poor prognosis disease with no clinically approved targeted therapies. Here, using in vitro and in vivo RNA interference (RNAi) screens in TNBC patient-derived xenografts (PDX), we identify cyclin dependent kinase 19 (CDK19) as a potential therapeutic target. Using in vitro and in vivo TNBC PDX models, we validated the inhibitory effect of CDK19 knockdown on tumor initiation, proliferation and metastases. Despite this, CDK19 knockdown did not affect the growth of non-transformed mammary epithelial cells. Using CD10 and EpCAM as novel tumor initiating cell (TIC) markers, we found the EpCAM med/high /CD10 −/low TIC sub-population to be enriched in CDK19 and a putative cellular target of CDK19 inhibition. Comparative gene expression analysis of CDK19 and CDK8 knockdowns revealed that CDK19 regulates a number of cancer-relevant pathways, uniquely through its own action and others in common with CDK8. Furthermore, although it is known that CDK19 can act at enhancers, our CHIP-Seq studies showed that CDK19 can also epigenetically modulate specific H3K27Ac enhancer signals which correlate with gene expression changes. Finally, to assess the potential therapeutic utility of CDK19, we showed that both CDK19 knockdown and chemical inhibition of CDK19 kinase activity impaired the growth of pre-established PDX tumors in vivo . Current strategies inhibiting transcriptional co-factors and targeting TICs have been limited by toxicity to normal cells. Because of CDK19’s limited tissue distribution and the viability of CDK19 knockout mice, CDK19 represents a promising therapeutic target for TNBC.
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There was a significant enrichment of genes whose knockdown by RNAi led to decreased viability of tumor cells in PDX models of TNBC (Q = 0.002, GSEA) among genes ordered by correlation with CytoTRACE in malignant LPs.
“In this rank-ordered list, we observed a significant enrichment of genes whose knockdown by RNA interference (RNAi) led to decreased viability of tumor cells in patient-derived xenograft (PDX) models of TNBC (41) (Q = 0.002, gene set enrichment analysis) (Fig. 4C; fig. S18, B and C, and table S8).”
From Single-cell transcriptional diversity is a hallmark of developmental potential (2020) · cites this paper as [41]
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Single-cell transcriptional diversity is a hallmark of developmental potential
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- Authors
- Hsieh, R. W., Kuo, A. H., Scheeren, F. A., Zarnegar, M. A., Sikandar, S. S., Antony, J., Heitink, L. S., Periyakoil, D., Kalisky, T., Sim, S., Qian, D., Malhotra, S. V., Somlo, G., Dirbas, F. M., Jadhav, A., Newman, A. M., & Clarke, M. F.
- Affiliations
- Stanford Medicine (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- Leiden University Medical Center (NL)
- City Of Hope National Medical Center (US)
- National Institutes of Health (US)
- Corresponding author
- Clarke, Michael F.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2018-05-10
- OpenAlex
- W2799839782
- Cited by
- 3
- References
- 47
- Citations by year
- 2025: 1 · 2020: 1 · 2019: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- U.S. Department of Defense (W81XWH1310281, W81XWH-11-1-, W81XWH, W81XWH1110287, W81XWH-13)
- Breast Cancer Research Foundation
- California Institute of Regenerative Medicine
- Ludwig Institute for Cancer Research
- National Institutes of Health (1s10rr029338-01, W81XWH)
- National Cancer Institute (CA100225)
- Stanford Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- CDK19, triple-negative breast cancer, cancer stem cells, EpCAM, CD10, CDK8, enhancer regulation, H3K27ac, transcriptional cofactors, patient-derived xenografts, therapeutic target, metastasis, tumor growth
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