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Comprehensive kinomic study via a chemical proteomic approach reveals kinome reprogramming in hepatocellular
Shufeng Wang1, Xinzheng Wang1, Xin Yang1
1National Center of Biomedical Analysis, Beijing, 100850, China.
Abstract:
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Kinases are attractive therapeutic targets since they are commonly altered in cancers. Here, to identify kinases of potential therapeutic interest in HCC, a quantitative kinomic study of tumour and adjacent non-tumour liver tissues was performed using a chemical proteomics approach. In total, 124 kinases were found differentially expressed and they were distributed over all nine kinase groups. Exploration of The Cancer Genome Atlas (TCGA) data showed that the dysregulation of 45 kinases was correlated with poor prognosis in HCC patients. We then tested 11 inhibitors targeting 12 crucial protein kinases alone or in combination for their ability to inhibit cell growth in Hep3B and PLC/PRF/5 cell lines. Six inhibitors significantly reduced viability in both cell lines. Combination inhibition of polo-like kinase 1 (PLK1) and casein kinase 1 epsilon (CSNK1E) significantly induced growth arrest in both cell lines synergistically. In summary, our analysis presents the most complete view of kinome reprogramming in HCC and provides novel insight into crucial kinases in HCC and potential therapeutic targets for HCC treatment. Moreover, the identification of hundreds of differentially expressed kinases forms a rich resource for novel drug targets or diagnostic biomarker discovery. Data are available via ProteomeXchange (identifier PXD023806).
Insights
This study identifies key protein kinases involved in hepatocellular carcinoma (HCC) progression. Combination therapy targeting polo-like kinase 1 and casein kinase 1 epsilon shows promise for HCC treatment.
Area of Science:
- Oncology
- Proteomics
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a prevalent global cancer.
- Protein kinases are frequently dysregulated in cancer and represent key therapeutic targets.
Purpose of the Study:
- To comprehensively analyze the kinome in HCC.
- To identify novel therapeutic targets and biomarkers for HCC treatment.
Main Methods:
- Quantitative kinomic profiling of HCC and adjacent non-tumour tissues using chemical proteomics.
- Analysis of The Cancer Genome Atlas (TCGA) data for kinase-prognosis correlation.
- In vitro testing of kinase inhibitors in HCC cell lines.
Main Results:
- 124 differentially expressed kinases identified across all nine kinase groups.
- Dysregulation of 45 kinases correlated with poor HCC patient prognosis.
- Six inhibitors demonstrated significant HCC cell growth inhibition; combination of PLK1 and CSNK1E inhibitors induced synergistic growth arrest.
Conclusions:
- This study provides the most complete view of kinome reprogramming in HCC to date.
- Identified crucial kinases and potential therapeutic targets for HCC.
- Highlights differentially expressed kinases as a resource for drug discovery and biomarker development.
