title: ASP5878, a selective FGFR inhibitor, to treat FGFR3-dependent urothelial cancer with or without chemoresistance.
abstract: FGF/FGFR gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers including urothelial cancer. FGFR kinase inhibitors are expected to be a targeted therapy for urothelial cancer harboring FGFR3 gene alternations. ASP5878, a selective inhibitor of FGFR1, 2, 3 and 4 under clinical investigation, selectively inhibited cell proliferation of urothelial cancer cell lines harboring FGFR3 point mutation or fusion (UM-UC-14, RT-112, RT4 and SW 780) among 23 urothelial cancer cell lines. Furthermore, ASP5878 inhibited cell proliferation of adriamycin-resistant UM-UC-14 cell line harboring MDR1 overexpression and gemcitabine-resistant RT-112 cell line. The protein expression of c-MYC, an oncoprotein, in gemcitabine-resistant RT-112 cell line was higher than that in RT-112 parental cell line and ASP5878 decreased the c-MYC expression in both RT-112 parental and gemcitabine-resistant RT-112 cell lines. Once-daily oral administration of ASP5878 exerted potent antitumor activities in UM-UC-14, RT-112 and gemcitabine-resistant RT-112 xenograft models without affecting body weight. These findings suggest that ASP5878 has the potential to be an oral targeted therapy against urothelial cancer harboring FGFR3 fusion or FGFR3 point mutation after the acquisition of gemcitabine- or adriamycin-resistance.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Masateru
authors.initials: M
authors.lastname: Iizuka
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kameda
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shindoh
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Terasaka
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hirano
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan.
authors.forename: Sadao
authors.initials: S
authors.lastname: Kuromitsu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D050939:Gene Fusion; D006801:Humans; D058990:Molecular Targeted Therapy; D017354:Point Mutation; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C513055:ABCB1 protein, human; C000615784:ASP5878; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C116115:MYCBP protein, human; D011720:Pyrazoles; D011743:Pyrimidines; D014157:Transcription Factors; D003841:Deoxycytidine; D004317:Doxorubicin; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D000093542:Gemcitabine
keywords: Chemotherapy; FGFR3-fusion or -mutation; molecular targeted drug therapy; oral dosing; urothelial cancer