Alcohol induces sorafenib resistance in hepatocellular carcinoma: A translational study

Alcohol is a major cause of hepatocellular carcinoma (HCC), accounting for 30% of cases worldwide. Sorafenib, a tyrosine kinase inhibitor (TKI), was the standard first-line treatment for advanced HCC until 2021, but sorafenib resistance is common. We explored the impact of chronic alcohol exposure (CAE) on sorafenib response and sought to identify associated resistance mechanisms. Huh-7 HCC cells were chronically exposed to alcohol for 6 months. Sorafenib resistance was assessed by measuring cell viability (IC50) and by evaluating the protein expression of signaling pathways involved in resistance using immunoblotting. RNA sequencing was performed to identify mechanisms of resistance. Sorafenib response was assessed using the RECIST 1.1 criteria in HCC patients. A retrospective study of 86 HCC patients from the CHIEF cohort (alcohol-related vs. non-alcohol-related etiologies) evaluated overall survival (OS) and progression-free survival (PFS) using the log-rank test. CAE significantly decreased cell sensitivity to sorafenib (p = 0.006), indicating increased resistance. The ERK pathway was involved. RNA sequencing of our cells identified a total of 80 differentially expressed genes associated with drug resistance and aggressiveness. Clinically, alcohol-related HCC patients were less responsive to sorafenib (35% responders vs. 65%, p = 0.014) and had significantly different OS (p = 0.0234). Median OS was 10 months (95% CI = [6.1, 15.7]) for alcohol-related HCC and 12.1 months (95% CI = [7.7, 64.9]) for other etiologies. PFS was lower in the alcohol group (5.72 months (95% CI = [4.63, 12.8]) vs. 9.66 months (95% CI = [4.40, 39.9], p = 0.0298). Sorafenib resistance due to chronic alcohol consumption is consistent in both in vitro models and clinical settings. KEY MESSAGES: Chronic alcohol exposure reduces the effectiveness of sorafenib in hepatocellular carcinoma (HCC), as demonstrated in both in vitro and clinical settings. In vitro, alcohol-exposed HCC cells showed increased sorafenib resistance, associated with activation of the ERK signaling pathway and differential expression of 80 genes linked to drug resistance and tumor aggressiveness. Clinically, patients with alcohol-related HCC had poorer responses to sorafenib and shorter overall and progression-free survival compared to patients with non-alcohol-related HCC. These findings suggest that alcohol-related HCC may require alternative or personalized therapeutic strategies beyond standard TKI treatments.