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Preclinical study reveals ALKBH5 upregulation promotes early sorafenib resistance in hepatocellular carcinoma, highlighting a target to overcome drug tolerance.
Hepatocellular carcinoma (HCC) frequently develops resistance to tyrosine kinase inhibitors (TKIs) like sorafenib – the first FDA-approved systemic therapy for advanced HCC – yet early resistance mechanisms remain unclear. Short-term sorafenib exposure in sensitive HCC cells induces global m6A reduction and rapid upregulation of the demethylase ALKBH5. High ALKBH5 expression correlates with poor prognosis in sorafenib-treated HCC patients. Functionally, ALKBH5 overexpression enhances sorafenib resistance, clonogenicity and epithelial-mesenchymal transition (EMT) by stabilizing β-catenin and activating Wnt/β-catenin signalling. Thus, ALKBH5 is a key early driver of sorafenib resistance via the Wnt/β-catenin pathway and may serve as both a prognostic biomarker and therapeutic target in HCC.
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Li et al. (2026) studied this question.
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