Background: FGFs (fibroblast growth factors) and their receptors (FGFRs) play crucial roles in regulation of cell proliferation, survival, migration and differentiation. Deregulation of FGFR expression has been reported in multiple cancers, including breast, bladder, lung, gastric, endometrial and multiple myeloma. FGFRs are overactivated by several mechanisms such as gene amplification, translocation and mutations. FGFR gene alterations are reported in a variety of cancers. We have identified a highly potent, irreversible and selective FGFR inhibitor, TAS-120 (1). In this report, we investigated FGFR turnover in human cancer cell lines. Moreover, we present the antitumor efficacy and pharmacodynamic (PD) activity of TAS-120 in xenograft tumor models to determine the optimal dosing schedule.

Materials and Methods: For in vitro turnover experiments, cell lines were treated with Brefeldin A which suppresses de novo protein synthesis. The cellular level of FGFR was determined by ELISA. For in animal efficacy studies, FGFR2 gene amplified human tumor cell lines were subcutaneously transplanted into the side flank of nude mice or rats. Dosing of compound was started when transplanted tumor size reached > ∼ 200 mm3. For antitumor efficacy, tumor size was measured with digital calipers. To determine the optimal dosing schedule of TAS-120 in a human tumor xenograft model, we orally administered TAS-120 by daily, every other day and other intermittent dosing schedule. The time course of phospho-FGFR inhibition in tumor after single dosing of TAS-120 was also examined as a pharmacodynamic marker.

Results: FGFR turnover was investigated in 2 human cancer cell lines, OCUM-2M (gastric cancer cell line with FGFR2 amplification) and OPM-2 (multiple myeloma cell line with FGFR3 gene translocation). When cells were treated with Brefeldin A, cellular FGFR levels were reduced to < 20% at 4 and 6 hr respectively. FGFR turnover in these cells is rapid as most FGFR protein was replaced within 4 or 6 hr. In animal studies, we determined the PD/efficacy correlation. The time course of phosphor-FGFR inhibition in tumor at efficacious doses suggests that continuous inhibition of the target is not necessary to maintain efficacy. Additional studies in OCUM-2MD3 and SNU-16 models demonstrated that TAS-120 is efficacious even with intermittent dosing schedules of every other day or twice/week schedule.

Conclusion: TAS-120 is a highly potent, selective, irreversible FGFR inhibitor, which demonstrated strong tumor growth inhibition across continuous and intermittent dosing schedules in mice and rat xenograft models.

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

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A272.

Citation Format: Yoko Nakatsuru, Hiroaki Ochiiwa, Hiroshi Sootome, Hidenori Fujita, Akihiro Hashimoto, Yoshihiro Shibata, Masato Chiba, Yayoi Fujioka, Kazuhiro Yonekura, Hiroshi Hirai, Teruhiro Utsugi. Intermittent treatment with TAS-120, an irreversible FGFR inhibitor, is effective in tumors harboring a FGFR gene abnormality. [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 A272.