Abstract 1376: Receptor tyrosine kinase (RTK) signaling pathway in preclinical thyroid cancer models: Antitumor and antiangiogenic activity of lenvatinib to target VEGFR/FGFR/RET
Authors: Tohyama Osamu , Matsui Junji , Kodama Kotaro , Sugi Naoko Hata , Kimura Takayuki , Okamoto Kiyoshi , Minoshima Yukinori , Iwata Masao , Funahashi Yasuhiro 
Published: August 2015

Abstract
Background: Inhibition of tumor angiogenesis through the vascular endothelial growth factor receptor (VEGFR) signaling and oncogenic RTK signaling is a promising therapeutic target in thyroid cancer. Lenvatinib mesilate (LEN) is the selective inhibitor of VEGFR1-3, and other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor receptors (FGFR1-4), the platelet-derived growth factor receptor (PDGFR) α, KIT, and RET. We studied the antitumor and antiangiogenic activity of LEN by using various thyroid cancer models.
Methods: Roles of RTK signaling pathways in 11 thyroid cancer (differentiated (DTC), medullary (MTC), and anaplastic (ATC)) cells were examined by testing antiproliferative activity of selective RTK inhibitors. Mutation profiling of DTC cells was done by MassARRAY systems. Antitumor and antiangiogenic (immunohistochemical staining of the endothelial cell marker CD31) activity of LEN was tested in s.c. xenograft models. Phosphorylation of molecules in the FGFR1 and RET signaling pathways was evaluated through Western blotting (WB). Pharmacodynamic (PD) biomarker analyses of VEGF and FGF signaling pathway in xenograft models by treatment of LEN were performed.
Results:
DTC: Molecular profiling in DTC cells showed K1 cells had BRAF V600E and PIK3CA mutation (E542K). Other DTC cells didn't have active tumor driver mutations. Among 5 DTC cells, only RO82-W-1 (W1) cell showed the selective sensitivity against LEN and FGFR selective inhibitors (PD166866 and PD173074). W1 cells overexpressed FGFR1 and LEN inhibited bFGF-induced phosphorylation of FGFR1, FRS2, MEK and ERK in W1 cells in vitro. LEN inhibited in vivo tumor growth and decreased microvessel density (MVD) in 5 human DTC xenografts. LEN decreased phosphorylation of FRS2, which a substrate FGFR, in W1 xenografts.
MTC: TT cells were reported to have activated mutation in RET. The IC50 value of LEN was 0.078 μM. Oral administration of LEN at dose of 10, 30 and 100 mg/kg inhibited in vivo tumor growth but did not decrease MVD in TT xenograft model. LEN inhibited phosphorylation of RET within TT xenograft at the same doses to show antitumor activity. ATC: LEN did not show anti proliferative activity against 5 ATC cells in vitro (IC50 value &gt; 10 μM). LEN showed the both antitumor and antiangiogenic activity in 5 ATC xenografts.
Conclusion: LEN showed the antitumor activity in 11 human thyroid cancer xenografts through antiangiogenic activity based on inhibition of VEGFR2 whereas inhibition of FGFR and RET signaling pathway contributes antitumor activity of LEN in some of DTC and MTC preclinical models. These data suggest that LEN provides therapeutic benefits in various human thyroid cancer models through VEGFR/FGFR/RET inhibitory activity.
Citation Format: Osamu Tohyama, Junji Matsui, Kotaro Kodama, Naoko Hata Sugi, Takayuki Kimura, Kiyoshi Okamoto, Yukinori Minoshima, Masao Iwata, Yasuhiro Funahashi. Receptor tyrosine kinase (RTK) signaling pathway in preclinical thyroid cancer models: Antitumor and antiangiogenic activity of lenvatinib to target VEGFR/FGFR/RET. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1376. doi:10.1158/1538-7445.AM2015-1376