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ResearchIn-Press PreviewOncologyTherapeutics Open Access | 10.1172/JCI176709
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Li, J. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Yueying, L. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Wang, L. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Liang, J. in: JCI | PubMed | Google Scholar |
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Ji, H. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Zhang, L. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Ding, X. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Chumanevich, A. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Mack, Z. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Schools, G. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Lim, C. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
Find articles by Porter, D. in: JCI | PubMed | Google Scholar
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America
2Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America
3Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Charleston, United States of America
4Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, BOSTON, United States of America
5Department of Bioinformatics, Semmelweis University, Budapest, Hungary
6Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, United States of America
7Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America
8Chao Cancer Center, University of California, Irvine, irvine, United States of America
9Senex Biotechnology, Inc., Columbia, United States of America
10Division of Hematology-Oncology, Medical University of South Carolina, Charleston, United States of America
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Published March 28, 2024 - More info
Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppresses the growth of CRPC xenografts but also induces tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplifies and modulates the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affects stromal gene expression, indicating that Mediator kinase activity in CRPC molds the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulates the MYC pathway, and Mediator kinase inhibition suppresses a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors show efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlates with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediate androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.