title: Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models.
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.
authors.affiliation: Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba, Ibaraki, 300-2635, Japan. Electronic address: k4-okamoto@hhc.eisai.co.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kodama
authors.forename: Kazuma
authors.initials: K
authors.lastname: Takase
authors.forename: Naoko Hata
authors.initials: NH
authors.lastname: Sugi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Masao
authors.initials: M
authors.lastname: Iwata
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tsuruoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; C088832:CCDC6 protein, human; D003598:Cytoskeletal Proteins; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C531958:lenvatinib
keywords: Anti-cancer drug; Lenvatinib; Lung cancer; RET inhibitor; Thyroid cancer; Xenograft model