Background: FGFs (fibroblast growth factors) and their receptors (FGFRs) play crucial roles in regulation of cell proliferation, survival, migration and differentiation. The FGFRs are comprised of four subtypes (FGFR1∼4) and their gene abnormalities such as gene amplification, translocation and mutations have been reported in multiple cancers including breast, bladder, lung, gastric, endometrial and multiple myeloma. We have identified a highly potent and selective irreversible FGFR inhibitor, TAS-1201) which inhibits all 4 subtypes of FGFR. In this report, we present the in vitro efficacy of this compound in tumor cells harboring the various FGFR gene abnormalities. In addition, we present the antitumor efficacy and pharmacodynamic (PD) activity of in vivo xenograft models.

Materials and Methods: For a growth inhibition assay, various tumor cells with FGFR gene abnormalities were treated with TAS-120 for 3 days, and living cells were determined by using CellTiter-Glo™ which measures cellular ATP. Cellular phosphorylation of FGFR and its inhibition by TAS-120 were assayed using ELISA (R&D Systems) or western blotting method. For analysis of in vivo antitumor efficacy, various tumor cell lines were subcutaneously implanted into the side flank of nude mice. Dosing of compound was started when transplanted tumor size reached > ∼ 200 mm3 and tumor size was measured with digital calipers for the entire treatment period. To confirm target engagement by TAS-120 in human tumor xenograft models, we determined FGFR phosphorylation in tumor as a pharmacodynamic marker. FGFR phoshorylation in tumor was determined by ELISA or western blotting.

Results: In a cell proliferation assay, TAS-120 selectively inhibited growth of human cancer cell lines with FGFR gene abnormalities. Growth of cell lines without FGFR abnormalities were not inhibited by TAS-120 treatment. TAS-120 inhibited cellular phosphorylation of FGFR as well as intercellular signaling pathways downstream of FGFR in these cells. In addition, TAS-120 inhibited tumor growth in human tumor xenograft mouse models and FGFR phosphorylation in tumor in a dose-dependent manner.

Conclusion: TAS-120 is a highly potent irreversible FGFR inhibitor. It selectively inhibited growth of human cancer cell lines selectively, in a FGFR gene abnormality-dependent manner. In addition, TAS-120 demonstrated tumor growth inhibition in mice xenograft models. PD assays suggested this compound inhibits FGFR activity in human tumor xenograft models.

1) 24th EORTC-NCI-AACR Symposium (2012) abstract #380 & #383

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A270.

Citation Format: Hiroaki Ochiiwa, Hidenori Fujita, Kimihiro Itoh, Hiroshi Sootome, Akihiro Hashimoto, Yayoi Fujioka, Yoko Nakatsuru, Nobuyuki Oda, Kazuhiko Yonekura, Hiroshi Hirai, Teruhiro Utsugi. TAS-120, a highly potent and selective irreversible FGFR inhibitor, is effective in tumors harboring various FGFR gene abnormalities. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A270.