Role of ATP-binding Cassette Transporters in Sorafenib Therapy for Hepatocellular Carcinoma: An Overview

Background: Molecular therapy with sorafenib remains the mainstay for advanced-stage hepatocellular carcinoma. Notwithstanding, treatment efficacy is low, with few patients ob-taining long-lasting benefits due to the high chemoresistance rate. Objective: To perform, for the first time, an overview of the literature concerning the role of adeno-sine triphosphate-binding cassette (ABC) transporters in sorafenib therapy for hepatocellular carci-noma. Methods: Three online databases (PubMed, Web of Science, and Scopus) were searched, from in-ception to October 2020. Study selection, analysis, and data collection were independently per -formed by two authors. Results: The search yielded 224 results; 29 were selected for inclusion. Most studies were pre-clini-cal, using HCC cell lines; three used human samples. Studies highlight the effect of sorafenib in de-creasing ABC transporters expression. Conversely, it is described the role of ABC transporters, par-ticularly multidrug resistance protein 1 (MDR-1), multidrug resistance-associated proteins 1 and 2 (MRP-1 and MRP-2) and ABC subfamily G member 2 (ABCG2) in sorafenib pharmacokinetics and pharmacodynamics, being key resistance factors. Combination therapy with naturally available or synthetic compounds that modulate ABC transporters may revert sorafenib resistance by increas-ing absorption and intracellular concentration. Conclusion: A deeper understanding of ABC transporters' mechanisms may provide guidance for developing innovative approaches for hepatocellular carcinoma. Further studies are warranted to translate the current knowledge into practice and paving the way to individualized therapy.