title: E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models.
abstract: The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630-9. ©2016 AACR.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.|Department of Genomics-Based Drug Discovery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Watanabe Miyano
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kodama
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyajima
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mikamoto
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kuramochi
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Setsuo
authors.initials: S
authors.lastname: Funasaka
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagao
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Naoko Hata
authors.initials: NH
authors.lastname: Sugi
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Minoshima
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Karoji
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Ohashi
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Yamane
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Okada
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsushima
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Iwata
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uenaka
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan. a-tsuruoka@hhc.eisai.co.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tsuruoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009026:Mortality; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor