Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models

Kiyoshi Okamoto; Kotaro Kodama; Kazuma Takase; Naoko Hata Sugi; Yuji Yamamoto; Masao Iwata; Akihiko Tsuruoka

doi:10.1016/j.canlet.2013.07.007

Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models

Cancer Lett. 2013 Oct 28;340(1):97-103. doi: 10.1016/j.canlet.2013.07.007. Epub 2013 Jul 12.

Authors

Kiyoshi Okamoto¹, Kotaro Kodama, Kazuma Takase, Naoko Hata Sugi, Yuji Yamamoto, Masao Iwata, Akihiko Tsuruoka

Affiliation

¹ Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba, Ibaraki, 300-2635, Japan. Electronic address: k4-okamoto@hhc.eisai.co.jp.

PMID: 23856031
DOI: 10.1016/j.canlet.2013.07.007

Abstract

RET gene fusions are recurrent oncogenes identified in thyroid and lung carcinomas. Lenvatinib is a multi-tyrosine kinase inhibitor currently under evaluation in several clinical trials. Here we evaluated lenvatinib in RET gene fusion-driven preclinical models. In cellular assays, lenvatinib inhibited auto-phosphorylation of KIF5B-RET, CCDC6-RET, and NcoA4-RET. Lenvatinib suppressed the growth of CCDC6-RET human thyroid and lung cancer cell lines, and as well, suppressed anchorage-independent growth and tumorigenicity of RET gene fusion-transformed NIH3T3 cells. These results demonstrate that lenvatinib can exert antitumor activity against RET gene fusion-driven tumor models by inhibiting oncogenic RET gene fusion signaling.

Keywords: Anti-cancer drug; Lenvatinib; Lung cancer; RET inhibitor; Thyroid cancer; Xenograft model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Transformation, Neoplastic / drug effects
Cell Transformation, Neoplastic / genetics
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism
Drug Screening Assays, Antitumor
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
NIH 3T3 Cells
Neoplasm Transplantation
Neoplasms / drug therapy*
Neoplasms / enzymology
Neoplasms / genetics
Oncogene Proteins, Fusion / antagonists & inhibitors*
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / metabolism
Phenylurea Compounds / pharmacology*
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-ret / antagonists & inhibitors*
Proto-Oncogene Proteins c-ret / genetics
Proto-Oncogene Proteins c-ret / metabolism
Quinolines / pharmacology*
Signal Transduction

Substances

Antineoplastic Agents
CCDC6 protein, human
Cytoskeletal Proteins
Oncogene Proteins, Fusion
Phenylurea Compounds
Protein Kinase Inhibitors
Quinolines
Proto-Oncogene Proteins c-ret
RET protein, human
lenvatinib