Comparative Response of HCC Cells to TKIs: Modified in vitro Testing and Descriptive Expression Analysis

Area of Science:

• Oncology
• Pharmacogenomics
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) treatment is evolving with checkpoint inhibitors (CPIs), but tyrosine kinase inhibitors (TKIs) remain crucial.
• Validated biomarkers for predicting TKI response in HCC are lacking, necessitating personalized treatment approaches.
• Identifying transcriptomic predictors can optimize 2nd and 3rd line HCC therapies.

Purpose of the Study:

• To investigate differential sensitivity of HCC cell lines to approved TKIs.
• To identify novel transcriptomic biomarkers for predicting TKI response in HCC.
• To explore personalized treatment strategies based on identified biomarkers.

Main Methods:

• Evaluated sensitivity of nine HCC cell lines to sorafenib, lenvatinib, regorafenib, and cabozantinib using growth rate inhibition concentrations (GR50).
• Performed differential gene expression and gene set enrichment analysis (GSEA) on sensitive and non-sensitive cell line subgroups.
• Identified a 14-biomarker signature to classify cell line response profiles.

Main Results:

• HCC cell lines exhibited varied sensitivities to different TKIs, with sorafenib and regorafenib showing closer GR50 values.
• Lenvatinib and cabozantinib treatments displayed more diverse GR50 values across cell lines.
• A 14-biomarker signature effectively discriminated three distinct TKI response profiles, linked to specific activated pathways.

Conclusions:

• Diverse responses to TKIs highlight the need for personalized treatment strategies in HCC.
• Distinct transcriptomic profiles correlate with TKI effectiveness, supporting pharmacogenomic approaches.
• Further studies are warranted to validate these transcriptomic strategies for personalized HCC therapy, particularly post-CPI treatment failure.