Synergistic Effect of Lenvatinib and Chemotherapy in Hepatocellular Carcinoma Using Preclinical Models

Abstract

Mingxun Wang,1,* Xinfei Yao,2,* Zhiyuan Bo,3,4,* Jiuyi Zheng,3 Haitao Yu,3 Xiaozai Xie,3 Zixia Lin,3 Yi Wang,5 Gang Chen,3,4 Lijun Wu3 1Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2The First Clinical College, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lijun Wu; Gang Chen, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]; [email protected]: The current study aimed to evaluate the synergistic efficacy of lenvatinib and FOLFOX (infusional fluorouracil (FU), folinic acid, and oxaliplatin) in hepatocellular carcinoma (HCC) using patient-derived xenograft (PDX) and PDX-derived organotypic spheroid (XDOTS) models in vivo and in vitro.Methods: PDX and matched XDOTS models originating from three patients with HCC were established. All models were divided into four groups and treated with drugs alone or in combination. Tumor growth in the PDX models was measured and recorded, and angiogenesis and phosphorylation of the vascular endothelial growth factor receptor (VEGFR2), rearranged during transfection (RET), and extracellular signal-regulated kinase (ERK) were detected using immunohistochemistry and Western blot assays. The proliferative ability of XDOTS was evaluated through active staining and immunofluorescence staining, and the effect of the combined medication was evaluated using the Celltiter-Glo luminescent cell viability assay.Results: Three PDX models with genetic characteristics similar to those of the original tumors were successfully established. Combining lenvatinib with FOLFOX led to a higher tumor growth inhibition rate than individual therapies (P < 0.01). Immunohistochemical analysis demonstrated that the combined treatment significantly inhibited the proliferation and angiogenesis of PDX tissues (P < 0.05), and Western blot analysis showed that the combined treatment significantly inhibited the phosphorylation of VEGFR2, RET, and ERK compared with single-agent treatment. Additionally, all three matched XDOTS models were successfully cultured with satisfactory activity and proliferation, and the combined therapies led to better suppression of XDOTS growth compared with individual therapy (P < 0.05).Conclusion: Lenvatinib combined with FOLFOX had a synergistic antitumor effect in HCC PDX and XDOTS models by inhibiting the phosphorylation of VEGFR, RET, and ERK.Keywords: hepatocellular carcinoma, lenvatinib, chemotherapy, patient-derived xenografts, angiogenesis

Keywords

• hepatocellular carcinoma
• lenvatinib
• chemotherapy
• patient-derived xenografts
• angiogenesis.