Network Pharmacology-Based Strategy to Investigate the Mechanisms of Lenvatinib in the Treatment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a complex and refractory malignant tumor, ranking the third cause of cancer-related deaths worldwide. Lenvatinib is currently employed to treat advanced, unresectable HCC as a first-line drug. The purpose of this study was to explore the pharmacological mechanisms of lenvatinib acting on HCC through the analysis of differential expressed genes based on network pharmacology. The target genes of lenvatinib were collected from PubChem, SwissTargetPrediction, PharmMapper, and BATMAN-TCM online public databases. In addition, related gene targets for HCC were obtained using NCBI Gene Expression Omnibus (NCBI-GEO) database. Afterward, the protein-protein interaction (PPI) network was established to visualize and understand the interaction relationships of overlapping gene targets from both lenvatinib and HCC. Furthermore, according to the data obtained, Gene Ontology (GO) analysis indicated that these intersectant genes were mainly enriched in response to xenobiotic stimulus, gland development, ion channel complex, membrane raft, and steroid binding. Besides, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that the therapeutic effects of lenvatinib on HCC probably involved bile secretion, MAPK signaling pathway, cGMP-PKG signaling pathway, PI3K-Akt signaling pathway, and Ras signaling pathway. Moreover, a total of six key differential genes, namely, ALB, CCND1, ESR1, AR, CCNA2, and AURKA, were identified as most significant targets associated with lenvatinib treating HCC and further verified by molecular docking, which demonstrated that lenvatinib had a strong binding efficiency with these six key gene-encoded proteins. Taken together, this study systematically provided new insights for researchers to determine the intervention mechanisms of lenvatinib in HCC therapy.

The role of Aurora kinase A in hepatocellular carcinoma: Unveiling the intriguing functions of a key but still underexplored factor in liver cancer

“…Lenvatinib is one of the first-line oral multikinase inhibitors for advanced HCC, targeting vascular endothelial growth factor receptor 1-3 (VEGFR1-3), fibroblast growth factor receptor 1-4 (FGFR1-4), platelet-derived growth factor receptor alpha (PDGFRA), KIT proto-oncogene, receptor tyrosine kinase (KIT), and rearranged during transfection (RET). 123,124 In the study, docking algorithms were used to predict the non-covalent interaction between molecular targets and the drug identifying AURKA as one of the possible targets of lenvatinib in HCC. 123 Over the years, various studies identified several compounds able to inhibit AURKA in vitro, with some accumulating sufficient evidence to undergo further evaluation as potential cancer therapies during preclinical or clinical trials.…”

“…123,124 In the study, docking algorithms were used to predict the non-covalent interaction between molecular targets and the drug identifying AURKA as one of the possible targets of lenvatinib in HCC. 123 Over the years, various studies identified several compounds able to inhibit AURKA in vitro, with some accumulating sufficient evidence to undergo further evaluation as potential cancer therapies during preclinical or clinical trials. The initial generation of AURKA inhibitors comprises ATP-competitive inhibitors that bind to the ATP binding pocket of AURKA, and currently represent the majority of AURKA inhibitors that have undergone clinical investigation.…”

“…A recent study investigated the pharmacological mechanisms and internal factors influencing the efficacy of lenvatinib in HCC treatment. Lenvatinib is one of the first‐line oral multikinase inhibitors for advanced HCC, targeting vascular endothelial growth factor receptor 1‐3 (VEGFR1‐3), fibroblast growth factor receptor 1‐4 (FGFR1‐4), platelet‐derived growth factor receptor alpha (PDGFRA), KIT proto‐oncogene, receptor tyrosine kinase (KIT), and rearranged during transfection (RET) 123,124 . In the study, docking algorithms were used to predict the non‐covalent interaction between molecular targets and the drug identifying AURKA as one of the possible targets of lenvatinib in HCC 123 …”

“… 123 , 124 In the study, docking algorithms were used to predict the non‐covalent interaction between molecular targets and the drug identifying AURKA as one of the possible targets of lenvatinib in HCC. 123 …”

Retracted: Network Pharmacology‐Based Strategy to Investigate the Mechanisms of Lenvatinib in the Treatment of Hepatocellular Carcinoma

“…Tis article has been retracted by Hindawi, as publisher, following an investigation undertaken by the publisher [1]. Tis investigation has uncovered evidence of systematic manipulation of the publication and peer-review process.…”