Background: Fibroblast growth factor (FGF) / FGF receptor (FGFR) gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers. Recently, FGFR3 fusions (FGFR3-TACC3 and FGFR3-BAIAP2L1), which have potent oncogenic activity, have been discovered in bladder and lung cancer. FGFR kinase inhibitors are expected to be a targeted therapy for bladder cancer harboring FGFR3 gene alternations. A phase I clinical trial of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, is ongoing (NCT02038673). Method: We tested selectivity of ASP5878 among 128 kinases and sensitivity of ASP5878 on cell proliferation of bladder cancer cell lines. FGFR3 and ERK phosphorylation in FGFR3-dependent bladder cancer cell lines were evaluated with sandwich ELISA or Western blotting. In vivo antitumor effects of ASP5878 were examined in subcutaneously implanted bladder cancer cell lines in nude mice. Results: Among 128 kinases, only 9 kinases including wild-type FGFR1-4 and FGFR3/4 mutants were inhibited more than 50% by ASP5878 (200 nmol/L). The IC50 values of ASP5878 against FGFR1, 2, 3 and 4 kinases are 0.47, 0.60, 0.74 and 3.5 nmol/L, respectively. In addition, ASP5878 suppressed cell growth in several cancer cell lines harboring FGF / FGFR gene alternations. Among 25 bladder cancer cell lines, ASP5878 selectively inhibited cell proliferation of UM-UC-14 [FGFR3 (S249C) positive], RT-112 (FGFR3-TACC3 positive), RT-4 (FGFR3-TACC3 positive) and SW780 (FGFR3-BAIAP2L1 positive). FGFR3 and ERK phosphorylation in UM-UC-14 and RT-112 cell lines were inhibited by ASP5878 in a concentration-dependent manner. Furthermore, ASP5878 inhibited cell proliferation of gemcitabine-resistant RT-112 cells and adriamycin-resistant UM-UC-14 cells. Once-daily oral administration of ASP5878 induced tumor regression at 1 and 3 mg/kg in UM-UC-14 and RT-112 xenograft models, respectively, without body weight loss. Conclusions: These findings suggest that ASP5878 has the potential to be an oral targeted therapy against bladder cancer harboring FGFR3-TACC3 fusion or FGFR3 point mutation even after the acquisition of chemoresistance.

Citation Format: Tomoyuki Suzuki, Aya Kikuchi, Taisuke Nakazawa, Masateru Iizuka, Ayako Nakayama, Minoru Kameda, Nobuaki Shindoh, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu. Preclinical antitumor activity of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, in bladder cancer harboring FGFR3-fusion or -mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A170.