Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors

Abstract

Sorafenib, a multikinase inhibitor with antiproliferative, antiangiogenic, and proapoptotic properties, constitutes the only effective first-line drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Despite its capacity to increase survival in HCC patients, its success is quite low in the long term owing to the development of resistant cells through several mechanisms. Among these mechanisms, the antiangiogenic effects of sustained sorafenib treatment induce a reduction of microvessel density, promoting intratumoral hypoxia and hypoxia-inducible factors (HIFs)-mediated cellular responses that favor the selection of resistant cells adapted to the hypoxic microenvironment. Clinical data have demonstrated that overexpressed HIF-1α and HIF-2α in HCC patients are reliable markers of a poor prognosis. Thus, the combination of current sorafenib treatment with gene therapy or inhibitors against HIFs have been documented as promising approaches to overcome sorafenib resistance both in vitro and in vivo. Because the depletion of one HIF-α subunit elevates the expression of the other HIF-α isoform through a compensatory loop, targeting both HIF-1α and HIF-2α would be a more interesting strategy than therapies that discriminate among HIF-α isoforms. In conclusion, there is a marked correlation between the hypoxic microenvironment and sorafenib resistance, suggesting that targeting HIFs is a promising way to increase the efficiency of treatment.

Fig. 1. Hypoxia-related mechanisms of sorafenib resistance and targeting strategies against HIFs

Sustained sorafenib treatment enhances hypoxia-inducible factors 1α or 2α, which promote the transcription of a wide range of genes involved in mitophagy, proliferation, glucose metabolism, angiogenesis, tumor invasion, and metastasis, leading to sorafenib resistance. This resistance can be overcome by different small molecules or drugs that inhibit HIFs. ADP, adenosine diphosphate; ATP, adenosine triphosphate; BNIP3, B-cell lymphoma-2 (BCL2)/adenovirus E1B 19 kDa-interacting protein 3; c-Myc, Myc proto-oncogene protein; CoA, coenzyme A; EGFR, phospho-epidermal growth factor receptor; GLUT-1, glucose transporter 1; HIF, hypoxia-inducible factor; HK2, hexokinase 2; LDHA, lactate dehydrogenase A; MDR1, multidrug resistance protein 1; NAD⁺, nicotinamide adenine dinucleotide (oxidized form); NADH, nicotinamide adenine dinucleotide (reduced form); NIX, BNIP3-like protein X; P, phosphate; PCNA, proliferating cell nuclear antigen; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase isoform 1; TGF-α, transforming growth factor α; TIP30, oxidoreductase HTATIP2; VEGF, vascular endothelial growth factor