Prognostic value of salt-inducible kinase 2 expression in advanced hepatocellular carcinoma treated with sorafenib or lenvatinib: a propensity score-matched cohort study.

Abstract

Hepatocellular carcinoma (HCC) requires reliable biomarkers to guide the use of sorafenib or lenvatinib for personalized first-line treatment. This study investigated the association between salt-inducible kinase 2 (SIK2) expression and treatment outcomes in patients with advanced HCC receiving these tyrosine kinase inhibitors (TKIs). A retrospective cohort of 120 patients who received treatment from January 2022 to December 2024 was included. The expression of SIK2 was evaluated by immunohistochemistry, and the optimal H-score cut-off value of 6 was determined by ROC analysis. After 1:1 propensity score matching, 47 patients with high SIK2 expression and 47 patients with low SIK2 expression were compared. Patients with high SIK2 expression showed a significantly superior objective response rate (36.2% vs. 12.8%, P<0.001) and disease control rate (87.2% vs. 57.4%, P<0.001), as well as prolonged median overall survival (15.4 vs. 9.5 months; HR = 0.30, P<0.001) and progression-free survival (7.8 vs. 3.7 months; HR = 0.38, P<0.001). Multivariate analysis confirmed that low SIK2 expression was an independent predictor of poor OS (adjusted HR = 2.22, P<0.05) and PFS (adjusted HR = 1.96, P<0.05). Subgroup analysis showed that the prognostic value of SIK2 was consistent in the sorafenib and lenvatinib groups, and there was no significant interaction (P for interaction >0.05). Safety analysis showed that the incidence of adverse events between the two groups was comparable, while patients with low SIK2 expression had significant increases in liver enzymes and bilirubin after treatment (all P<0.05). In conclusion, low SIK2 expression independently predicts poor therapeutic response and survival in advanced HCC patients receiving first-line sorafenib or lenvatinib, with consistent predictive value across both TKIs. SIK2 represents a promising common predictive biomarker to guide personalized first-line targeted therapy for HCC.