Background: Targeting protein kinases with irreversible small molecule inhibitors is moving to the forefront in cancer therapy. Irreversible kinase inhibitors may achieve superior potency, selectivity and longer duration of action compared to conventional reversible inhibitors, and may provide an effective approach to overcome drug resistance caused by mutations within drug binding sites1). TAS-120, a highly potent and selective irreversible FGFR inhibitor shows activity against tumors harboring FGFR gene abnormalities2). In this study, we aim at getting evidence to support the concept as “overcomer of acquired resistance” and to confirm the advantage of TAS-120 over ATP competitive inhibitor “A”.

Materials and Methods: N550H and E566G mutations in the FGFR2 hinge region were reported to cause resistance to dovitinib3). The K660M within the FGFR2 activation loop is an activating mutation reported in cervical cancer. V565 was made into V565I as a model of gatekeeper mutant. These mutants were transduced to HEK293T cells and the effect of TAS-120 was determined by phospho-FGFR2 ELISA. To isolate resistant cell clones, OCUM-2MD3 cells (FGFR2 amplified human gastric cancer cell line) were treated with either TAS-120 or ATP competitive FGFR inhibitor “compound A” at increasing concentrations for several months. Following clonal selection, the kinase domain of FGFR2 in resistant clones was sequenced.

Results: Inhibitory potencies of tested ATP competitive inhibitors against four FGFR2 mutants were reduced compared to that against wild type. In contrast, TAS-120 retained inhibitory potency to all mutations with the similar potency as when compared to wild type. The appearance or frequency of acquired resistance clones to TAS-120 was quite lower compared with what was observed with ATP competitive inhibitor “A”. Resistant clones to inhibitor “A” possessed a single mutation in the activation loop at a frequency of more than 60%. TAS-120 strongly inhibited the cell growth of these resistant clones carrying an FGFR2 mutation with similar potency as seen in wild type.

Conclusion: TAS-120 was effective to tumors harboring FGFR mutations, which were resistant to ATP competitive FGFR inhibitors. TAS-120 is expected to be effective in tumors refractory or resistant to ATP competitive FGFR inhibitors due to a mutation in FGFR kinase domain. In addition, appearance of drug-resistance compared to ATP competitive inhibitors may also be lower. These potential advantages of TAS-120 over ATP competitive FGFR inhibitors provide a strong rationale to accelerate the development of TAS-120 for the treatment of advanced cancers which are addicted to FGFR pathway.

1) Nat Rev Drug Discov. 2011;10: 307-17, 2) 24th EORTC-NCI-AACR Symposium (2012) abstract #380 & #383, 3) Proceedings of the 102nd Annual Meeting of the AACR (2011) abstract #4733

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A271.

Citation Format: Hiroshi Sootome, Yayoi Fujioka, Akihiro Miura, Hidenori Fujita, Hiroshi Hirai, Teruhiro Utsugi. TAS-120, an irreversible FGFR inhibitor, was effective in tumors harboring FGFR mutations, refractory or resistant to ATP competitive inhibitors . [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 A271.