Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo

Abstract

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor(TKI) of VEGFR1-VEGFR3, FGFR1-FGFR4, PDGFRα, RET and v-kit Hardy-Zuckerman4 feline sarcoma viral oncogene homolog(KIT) signaling networks involved in tumor angiogenesis. We have evaluated the antitumor activity of lenvatinib in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF). The AF cell line was obtained from the primary ATC cultures and was the one that grew over 50passages. The effect of lenvatinib (1 and 100nM; and 1, 10, 25 and 50µM) was investigated in primary ATC, 8305C and AF cells as well as in AF cells in CDnu/nu mice. Lenvatinib significantly reduced ATC cell proliferation(P<0.01, ANOVA) and increased the percentage of apoptotic ATC cells (P<0.001, ANOVA). Furthermore, lenvatinib inhibited migration (P<0.01) and invasion(P<0.001) in ATC. In addition, lenvatinib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclinD1 in the ATC cells. Lenvatinib also significantly inhibited 8305C and AF cell proliferation, increasing apoptosis. AF cells were subcutaneously injected into CDnu/nu mice and tumor masses were observed 20days later. Tumor growth was significantly inhibited by lenvatinib(25mg/kg/day), as well as the expression of VEGF-A and microvessel density in the AF tumor tissues. In conclusion, the antitumor and antiangiogenic activities of lenvatinib may be promising for the treatment of anaplastic thyroid cancer, and may consist a basis for future clinical therapeutic applications.