ArticleThe Journal of clinical investigation2024
Mediator kinase inhibition reverses castration resistance of advanced prostate cancer.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 21 citations in OpenAlex.
- Integrated Transcriptomic Analysis Identifies Potential Biomarkers in Castration-Resistant Prostate Cancer.World journal of oncology · 2026Article
- Anoikis resistance and metastasis of ovarian cancer can be overcome by CDK8/19 mediator kinase inhibition.JCI insight · 2026Article
- NUDT21-mediated Alternative Polyadenylation of CDK19 Reprograms Cholesterol Biosynthesis to Drive Colorectal Cancer Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Inhibition of CDK8 rescues impaired ischemic fracture healing.NPJ Regenerative medicine · 2026Article
- Targeting CDK8 dually enhances paclitaxel antitumor efficacy and alleviates chemotherapy-induced peripheral neuropathy in breast cancer.Frontiers in pharmacology · 2026Article
- Targeting Transcriptional Cyclin-Dependent Kinases in Cancer.Molecular cancer therapeutics · 2025Review
- Cyclin-dependent kinases as mediators of aberrant transcription in prostate cancer.Translational oncology · 2025Review
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- CDK8/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells.Cell death discovery · 2025Article
- Application of Original Prostate Cancer Progression Model Interacting with Fibroblasts in Preclinical Research.Journal of clinical medicine · 2024Review
- Mediator kinase inhibitors suppress triple-negative breast cancer growth and extend tumor suppression by mTOR and AKT inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- MED12 and CDK8/19 Modulate Androgen Receptor Activity and Enzalutamide Response in Prostate Cancer.Endocrinology · 2024Article
- Special Issue "Novel Chemical Tools for Targeted Cancer Therapy".International journal of molecular sciences · 2024Article
Corrections and comments
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Authors and funding
26 authors at 6 institutions in 2 countries.
Funding
Abstract
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 suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.