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 obtaining 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 adenosine triphosphate-binding cassette (ABC) transporters in sorafenib therapy for hepatocellular carcinoma. METHODS Three online databases (PubMed, Web of Science and Scopus) were searched, from inception to October 2020. Studies selection, analysis and data collection was independently performed by two authors. RESULTS The search yielded 224 results; 29 were selected for inclusion. Most studies were pre-clinical, using HCC cell lines; three used human samples. Studies highlight the effect of sorafenib in decreasing ABC transporters expression. Conversely, it is described the role of ABC transporters, particularly 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 increasing 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.