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Updated: May 12, 2026
A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma
Published on: September 30, 2021
Molecular determinants of outcome in sorafenib-treated patients with hepatocellular carcinoma
Nicola Personeni1, Lorenza Rimassa, Tiziana Pressiani
1Department of Oncology-Hematology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Mi, Italy. nic_personeni@hotmail.com
Purpose:
Preclinical studies show that sorafenib, a multitarget kinase inhibitor, displays anti-proliferative, anti-angiogenic, and pro-apoptotic properties in hepatocellular carcinoma (HCC). However, the determinants of sorafenib sensitivity in vivo remain largely unknown.
Methods:
We assessed the expression of Mcl-1, activated/phosphorylated extracellular signal-regulated kinase (pERK) 1/2, and activated/phosphorylated AKT (pAKT) in pretreatment tumor specimens from 44 patients with advanced HCC who received sorafenib. Furthermore, we assessed MYC and MET gene copy numbers (GCN) by fluorescence in situ hybridization.
Results:
Poorer overall survival (OS) times were correlated with pERK expression [hazard ratio (HR) 1.013; 95 % CI 1.003-1.035] and Mcl-1 expression (HR 1.016; 95 % CI 1.002-1.030) in pretreatment tumor samples. Expression levels of pERK and Mcl-1, however, were not correlated with time to tumor progression (TTP). Increased pERK expression was positively associated with higher Cancer of Liver Italian Program scores (P = 0.012) and was prognostic in patients with scores 2-6 but not in those with scores 0-1. pERK expression was significantly less frequent in specimens sourced from previous surgical procedures compared to biopsy samples (9.6 vs. 92.3 %, respectively; P < 0.0001). Analysis of pAKT expression, MET and MYC GCN, did not indicate any prognostic nor predictive values for these biomarkers in terms of survival.
Conclusions:
Expression levels of Mcl-1 and pERK are associated with reduced OS in HCC patients treated with sorafenib and might be useful markers for risk stratification. However, in contrast to previous findings, pERK expression levels, as well as other biomarkers tested, did not affect TTP.
Insights
Markers like Mcl-1 and phosphorylated extracellular signal-regulated kinase (pERK) indicate poorer overall survival (OS) in hepatocellular carcinoma (HCC) patients treated with sorafenib. These biomarkers may aid in risk stratification for HCC patients.
Area of Science:
- Hepatocellular Carcinoma Research
- Molecular Oncology
- Biomarker Discovery
Background:
- Sorafenib is a multitarget kinase inhibitor with preclinical anti-cancer properties in hepatocellular carcinoma (HCC).
- The factors influencing sorafenib sensitivity in HCC patients remain largely undetermined.
- Identifying predictive biomarkers is crucial for optimizing HCC treatment strategies.
Purpose of the Study:
- To investigate the role of Mcl-1, phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated AKT (pAKT), and gene copy numbers of MYC and MET as determinants of sorafenib sensitivity in advanced HCC.
- To assess the prognostic and predictive values of these potential biomarkers in relation to overall survival (OS) and time to tumor progression (TTP).
Main Methods:
- Analysis of Mcl-1, pERK, and pAKT expression in pretreatment tumor specimens from 44 advanced HCC patients receiving sorafenib.
- Assessment of MYC and MET gene copy numbers using fluorescence in situ hybridization.
- Correlation of biomarker expression with clinical outcomes, including OS and TTP.
Main Results:
- Higher expression of Mcl-1 and pERK in pretreatment tumors was significantly correlated with poorer overall survival (OS) in HCC patients treated with sorafenib.
- pERK expression was associated with higher Cancer of Liver Italian Program scores and showed prognostic value in specific patient subgroups.
- No significant correlation was found between Mcl-1 or pERK expression and time to tumor progression (TTP), nor did pAKT, MET, or MYC GCN show prognostic or predictive value.
Conclusions:
- Mcl-1 and pERK expression levels are associated with reduced OS in sorafenib-treated HCC patients and may serve as valuable markers for risk stratification.
- Contrary to some previous findings, pERK expression did not impact TTP, suggesting a complex role in HCC progression.
- Further research is needed to fully elucidate the predictive and prognostic roles of these biomarkers in HCC management.
