The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects

Abstract

Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.

Fig. 1

Molecular mechanisms by which lncRNAs and miRNAs modulate sorafenib resistance. a LncRNAs can act as a “sponge” of miRNAs, competitively binding miRNAs, and thus affect the regulation of miRNAs on downstream target genes. The figure lists the lncRNAs and corresponding sponged miRNAs associated with SR. b As a scaffold or bridge for protein interaction, lncRNAs affect the formation of protein multimers and regulate protein activity. c As an RNA decoy, lncRNAs bind to transcription factors and interfere with their binding to the gene promoter region, thereby regulating transcription. d LncRNAs recruit chromatin modifiers to alter the level of chromatin modification, thereby affecting gene transcription and expression. e LncRNAs bind to mRNA and inhibit translation. f MiRNAs have the ability to degrade mRNA and prevent mRNA translation. The figure lists the miRNAs associated with SR. Note: A pentagram indicates no relative report with SR in HCC

Fig. 2

Exosome application in HCC therapy. Exosomes derived from cancer cells can be used to deliver functional RNAs, including lncRNAs, siRNAs, miRNAs, and mRNAs

Fig. 3

Schematic diagram of autophagy flux. Autophagy is initiated (primed) by the nucleation of a membrane or phage. This process is initiated by the ULK1-Atg13-FIP200 complex. The membrane is then elongated to engulf the cytoplasmic component (elongation). The elongation of the phagocytic membrane depends on the Atg5-Atg12-Atg16 and LC3 coupling systems. At a later stage of autophagosome formation, LC3-II is localized to the elongated barrier membrane, while the Atg5-Atg12-Atg16 complex dissociates therefrom. Finally, the barrier membrane is closed to form autophagosomes. After autophagosome formation, lysosomes fuse with autophagosomes to form autolysosomes (autophagosome–lysosome fusions). The lysosomal hydrolase degrades the content (degradation) in the autophagosome. Beclin 1-VPS34-UVRAG complex positively regulates fusion and degradation

Fig. 4

The mechanisms of ferroptosis and sorafenib resistance. The key factor leading to ferroptosis are ROS, which are produced by iron accumulation and lipid peroxidation. This figure shows the relevant pathways that regulate iron and lipid peroxidation. SLC3A2 solute carrier family 3 member 2, SLC7A11 solute carrier family 7 member 11, BSO L-buthionine-sulfoximine, GPX4 glutathione peroxidase 4, PUFA polyunsaturated fatty acids, LOX lipoxygenase, NCOA4 nuclear receptor coactivator 4, PHKG2 phosphorylase kinase G2, HSPB1 heat shock protein family B (small) member 1, IREB2 iron-responsive element-binding protein 2

Fig. 5

Hypoxia-related sorafenib resistance mechanisms and strategies for targeting HIFs. Sustained sorafenib treatment enhances hypoxia-inducible factors 1 alpha and 2 alpha, thereby promoting transcription of multiple genes involved in proliferation, glucose metabolism, angiogenesis, and different pathways, leading to sorafenib resistance. This resistance can be overcome by different small molecules or drugs inhibiting HIFs

Fig. 6

Schematic diagram of the sorafenib resistance-mediated immune mechanism. CD8⁺ CTL cells, NK cells, DC cells, and macrophages have been confirmed to be involved in sorafenib resistance through different mechanisms