ArticleHepatology (Baltimore, Md.)2019
Inhibition of Cyclin-Dependent Kinase 5: A Strategy to Improve Sorafenib Response in Hepatocellular Carcinoma Therapy.
Article in Hepatology (Baltimore, Md.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 67 citations in OpenAlex.
- Sorafenib nanomedicine in HCC: nano-bio interactions and combination therapies.Journal of nanobiotechnology · 2026Review
- CDK5 targets p21Molecular medicine reports · 2025Article
- CDK5: Insights into its roles in diseases.Molecular biology reports · 2025Review
- The Potential Therapeutic Applications of CRISPR/Cas9 in the Treatment of Gastrointestinal Cancers.Current molecular medicine · 2025Review
- Prognostic value of oxidative phosphorylation-related genes in hepatocellular carcinoma.Discover oncology · 2024Article
- LARP4B promotes hepatocellular carcinoma progression and impairs sorafenib efficacy by activating SPINK1-mediated EGFR pathway.Cell death discovery · 2024Article
- Maintaining Drosha expression with Cdk5 inhibitors as a potential therapeutic strategy for early intervention after TBI.Experimental & molecular medicine · 2024Article
- CRISPR in Targeted Therapy and Adoptive T Cell Immunotherapy for Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2024Review
- STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice.Science signaling · 2023Article
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- CRISPR/Cas9 system: a reliable and facile genome editing tool in modern biology.Molecular biology reports · 2022Review
- Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma.Cell death & disease · 2022Article
- CRISPR/Cas9 gene editing: a new approach for overcoming drug resistance in cancer.Cellular & molecular biology letters · 2022Review
- Chenodeoxycholic Acid Enhances the Effect of Sorafenib in Inhibiting HepG2 Cell Growth Through EGFR/Stat3 Pathway.Frontiers in oncology · 2022Article
- Advanced Nanotheranostics of CRISPR/Cas for Viral Hepatitis and Hepatocellular Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Review
- Strategies to improve sorafenib efficacy during image-guided treatment of hepatocellular carcinoma.Annals of translational medicine · 2021Review
- Elevated CDK5R1 predicts worse prognosis in hepatocellular carcinoma based on TCGA data.Bioscience reports · 2021Article
- CRISPR/Cas9 in Gastrointestinal Malignancies.Frontiers in cell and developmental biology · 2021Review
- Elucidating the Molecular Basis of Sorafenib Resistance in HCC: Current Findings and Future Directions.Journal of hepatocellular carcinoma · 2021Review
Corrections and comments
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Authors and funding
22 authors at 9 institutions in 4 countries.
Funding
Abstract
Therapeutic options for patients with advanced-stage hepatocellular carcinoma (HCC) are very limited. The only approved first-line treatment is the multi-tyrosine kinase inhibitor sorafenib, which shows low response rates and severe side effects. In particular, the compensatory activation of growth factor receptors leads to chemoresistance and limits the clinical impact of sorafenib. However, combination approaches to improve sorafenib have failed. Here we investigate the inhibition of cyclin-dependent kinase 5 (Cdk5) as a promising combination strategy to improve sorafenib response in HCC. Combination of sorafenib with Cdk5 inhibition (genetic knockdown by short hairpin RNA or CRISPR/Cas9 and pharmacologic inhibition) synergistically impaired HCC progression in vitro and in vivo by inhibiting both tumor cell proliferation and migration. Importantly, these effects were mediated by a mechanism for Cdk5: A liquid chromatography-tandem mass spectrometry-based proteomic approach revealed that Cdk5 inhibition interferes with intracellular trafficking, a process crucial for cellular homeostasis and growth factor receptor signaling. Cdk5 inhibition resulted in an accumulation of enlarged vesicles and respective cargos in the perinuclear region, considerably impairing the extent and quality of growth factor receptor signaling. Thereby, Cdk5 inhibition offers a comprehensive approach to globally disturb growth factor receptor signaling that is superior to specific inhibition of individual growth factor receptors. Conclusion: Cdk5 inhibition represents an effective approach to improve sorafenib response and to prevent sorafenib treatment escape in HCC. Notably, Cdk5 is an addressable target frequently overexpressed in HCC, and with Dinaciclib, a clinically tested Cdk5 inhibitor is readily available. Thus, our study provides evidence for clinically evaluating the combination of sorafenib and Dinaciclib to improve the therapeutic situation for patients with advanced-stage HCC.
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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.