Antitumor Activity of Lenvatinib (E7080): An Angiogenesis Inhibitor That Targets Multiple Receptor Tyrosine Kinases in Preclinical Human Thyroid Cancer Models

Abstract

Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor (VEGF) signaling pathway is a promising therapeutic strategy for thyroid cancer. Lenvatinib mesilate (lenvatinib) is a potent inhibitor of VEGF receptors (VEGFR1–3) and other prooncogenic and prooncogenic receptor tyrosine kinases, including fibroblast growth factor receptors (FGFR1–4), platelet derived growth factor receptor α (PDGFRα), KIT, and RET. We examined the antitumor activity of lenvatinib against human thyroid cancer xenograft models in nude mice. Orally administered lenvatinib showed significant antitumor activity in 5 differentiated thyroid cancer (DTC), 5 anaplastic thyroid cancer (ATC), and 1 medullary thyroid cancer (MTC) xenograft models. Lenvatinib also showed antiangiogenesis activity against 5 DTC and 5 ATC xenografts, while lenvatinib showed in vitro antiproliferative activity against only 2 of 11 thyroid cancer cell lines: that is, RO82-W-1 and TT cells. Western blot analysis showed that cultured RO82-W-1 cells overexpressed FGFR1 and that lenvatinib inhibited the phosphorylation of FGFR1 and its downstream effector FRS2. Lenvatinib also inhibited the phosphorylation of RET with the activated mutation C634W in TT cells. These data demonstrate that lenvatinib provides antitumor activity mainly via angiogenesis inhibition but also inhibits FGFR and RET signaling pathway in preclinical human thyroid cancer models.

Lenvatinib induces early tumor shrinkage in patients with advanced thyroid carcinoma

“…It is an oral multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR)1-3, fibroblast growth factor receptor (FGFR)1-4, platelet-derived growth factor receptor alpha (PDGFR-α), ret proto-oncogene (RET), and KIT proto-oncogene [3][4][5]. In the phase 3 trial, lenvatinib prolonged progression-free survival (PFS; hazard ratio for progression or death, 0.21; 99 %CI, 0.14-0.31, p<0.001) by 14.7 months (lenvatinib median PFS, 8.3 months) compared with placebo (median PFS, 3.6 months) [6].…”

Animal models of medullary thyroid cancer: state of the art and view to the future

“…When tumours became palpable and mean tumour volume was approximately 70-80 mm 3 , animals were randomly divided into control group and treated group (Broutin et al 2011, Bentzien et al 2013, Lopergolo et al 2014, Tohyama et al 2014.…”

“…This molecule showed to inhibit the in vivo tumour growth of TT xenografts in a dose-dependent manner. Together with the antitumor activity, lenvatinib showed a potent inhibition in tumour-induced angiogenesis (Tohyama et al 2014).…”

Resistance to Kinase Inhibitors in Poorly Differentiated and Anaplastic Thyroid Cancer: Preclinical In vitro Evidences

“…However, despite the marked inhibition of tumor growth in vivo, lenvatinib shown antiproliferative activity in vitro in only 2 of 11 thyroid cancer cell lines (RO82-W-1 and TT). The authors discovered that cell response to lenvatinib was associated to direct inhibition of FGFR and RET signaling pathway, which are activated in RO82-W-1 and TT cell lines, respectively [28].…”