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Inhibition of Cyclin‐Dependent Kinase 5: A Strategy to Improve Sorafenib Response in Hepatocellular Carcinoma Therapy
- Source :
- Hepatology (Baltimore, Md.)
- Publication Year :
- 2018
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2018.
-
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.
- Subjects :
- 0301 basic medicine
Sorafenib
Carcinoma, Hepatocellular
Cellular homeostasis
Small hairpin RNA
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Growth factor receptor
Liver Biology/Pathobiology
Tumor Cells, Cultured
medicine
Animals
Humans
Dinaciclib
Protein Kinase Inhibitors
neoplasms
Gene knockdown
Hepatology
business.industry
Cyclin-dependent kinase 5
Liver Neoplasms
Cyclin-Dependent Kinase 5
Original Articles
medicine.disease
digestive system diseases
Treatment Outcome
030104 developmental biology
nervous system
chemistry
Hepatocellular carcinoma
Cancer research
Original Article
Female
030211 gastroenterology & hepatology
business
medicine.drug
Subjects
Details
- ISSN :
- 15273350 and 02709139
- Volume :
- 69
- Database :
- OpenAIRE
- Journal :
- Hepatology
- Accession number :
- edsair.doi.dedup.....b6c49ca1d32d238f3a1d3266d033ee1a
- Full Text :
- https://doi.org/10.1002/hep.30190