Comparative response of HCC cells to sorafenib, lenvatinib, cabozantinib and regorafenib; descriptive expression analysis

Introduction There are several tyrosine kinase inhibitors (TKI) currently approved for treatment of hepatocellular carcinoma (HCC), which will represent the future backbone of HCC treatment alone or in combination with immune checkpoint-inhibitors (CPI). The use of TKIs and their sequence of application in different lines of treatment is currently determined by empirical evidence, and no established biomarker capable of predicting the likelihood of response of one specific treatment exists. Thus, we examined differential sensitivity and investigated potential transcriptomic predictors of sensitivity to different TKIs.

Methods To this aim, the sensitivity of nine HCC cell lines to sorafenib, cabozantinib, lenvatinib and regorafenib was evaluated by proliferation assay to determine their respective growth rate inhibition concentrations (GR50). Subgroups discriminated by GR50 values underwent differential expression and gene set enrichment analysis (GSEA).

Results The nine cell lines showed broadly different sensitivity to different TKIs. GR50 values of sorafenib and regorafenib clustered closer in all cell lines, whereas treatment with lenvatinib and cabozantinib showed diversified GR50 values. GSEA showed the activation of specific pathways in sensitive vs. non-sensitive cell lines. A signature consisting of 15 biomarkers discriminates the cell lines’ response into three distinct treatment profiles: 1) equally sensible to sorafenib, regorafenib, and cabozantinib, 2) sensible to lenvatinib and 3) more sensible to regorafenib than sorafenib.

Outlook Different sensitivities to TKIs are connected to distinct transcriptomic profiles and signaling pathways. This prompts larger studies to validate this expression signature for predicting a treatment’s response for a personalized HCC treatment approach.

Publication History

Article published online:
26 January 2022