TAS-120 is a highly bioavailable, selective, and irreversible fibroblast growth factor receptor (FGFR) inhibitor that demonstrates potent inhibitory activity against FGFR1-4, with IC₅₀ values of 3.9nM, 1.3nM, 1.6nM, and 8.3nM[1-2]. TAS-120 covalently binds to a highly conserved cysteine residue in the P-loop of the FGFR ATP-binding pocket, leading to irreversible inhibition, suppression of FGFR-mediated signaling pathways, inhibition of tumor cell proliferation, and promotion of cell death in FGFR-expressing tumor cells[3-4].
In vitro, treatment of MCF10A cells expressing FGFR2-BICC1 fusion, FGFR2 Y375C mutation, or wild-type FGFR2 with TAS-120 (0-100μM) for 4 days, TAS-120 significantly inhibited phosphorylation of FGFR2, ERK1/2, Akt. TAS-120 reduced cell viability (IC₅₀ values of 18nM, 137nM, and 18μM, respectively). In FGFR2 Y375C-mutated PDX.007CL cells, TAS-120 also significantly inhibited cell proliferation (IC₅₀ of 0.48μM)[5]. Treatment of Ba/F3 cells expressing TEL-FGFR4 or RMS559 rhabdomyosarcoma cells harboring the FGFR4 V550L mutation with TAS-120 (0-20μM) for 72 hours, TAS-120 significantly suppressed FGFR4 autophosphorylation and the ERK1/2 signaling pathway, induced apoptosis, and inhibited colony formation[6].
In vivo, in an FGFR2-expressing OCUM-2MD3 gastric cancer xenograft model, oral administration of TAS-120 (0.15, 0.5, 1.5, and 5mg/kg; once daily for 14 days) dose-dependently and significantly inhibited tumor growth, with no signs of early resistance observed during treatment[7]. In an FGFR2-KIAA1217 fusion-positive patient-derived xenograft (PDX) model (MG69), oral treatment with TAS-120 (25mg/kg; once daily) resulted in tumor regression and complete suppression of proliferation, with effects evident within 3 days and sustained for 14 days, accompanied by inhibition of downstream MEK/ERK and SHP2 signaling pathways[8].
References:
[1] Kalyukina M, Yosaatmadja Y, Middleditch MJ, et al. TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem. 2019 Feb 19;14(4):494-500.
[2] Wu Q, Ellis H, Siravegna G, et al. Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma. Clin Cancer Res. 2024 Jan 5;30(1):198-208.
[3] Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med. 2023 Jan 19;388(3):228-239.
[4] Facchinetti F, Loriot Y, Brayé F, et al. Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies. Clin Cancer Res. 2024 Nov 1;30(21):4943-4956.
[5] Saridogan T, Akcakanat A, Zhao M, et al. Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer. Sci Rep. 2023 Nov 18;13(1):20223.
[6] Wu JT, Cheuk A, Isanogle K, et al. Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma. Cancers (Basel). 2023 Aug 9;15(16):4034.
[7] Sootome H, Fujita H, Ito K, et al. Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020 Nov 15;80(22):4986-4997.
[8] Goyal L, Shi L, Liu LY, et al. TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion-Positive Intrahepatic Cholangiocarcinoma. Cancer Discov. 2019 Aug;9(8):1064-1079.
TAS-120是一种口服生物利用度高、选择性强、不可逆的成纤维细胞生长因子受体（FGFR）抑制剂，可降低FGFR1-4的活性（IC₅₀分别为3.9nM、1.3nM、1.6nM和8.3nM）[1-2]。TAS-120通过与FGFR的ATP口袋中高度保守的P环半胱氨酸残基共价结合，实现不可逆抑制，从而抑制FGFR介导的信号传导通路和肿瘤细胞增殖，并促进表达FGFR的肿瘤细胞死亡[3-4]。
在体外，TAS-120（0-100μM）处理表达FGFR2-BICC1融合、FGFR2 Y375C突变或FGFR2野生型的MCF10A细胞4天，TAS-120显著抑制FGFR2及ERK1/2和Akt的磷酸化，并降低细胞活力（IC50分别为18nM、137nM和18μM）；在FGFR2 Y375C突变的PDX.007CL细胞中，TAS-120也显著抑制细胞增殖（IC50为0.48μM）[5]。TAS-120（0-20μM）处理表达TEL-FGFR4的Ba/F3细胞或携带FGFR4 V550L突变的RMS559横纹肌肉瘤细胞72小时，TAS-120显著抑制FGFR4自磷酸化及ERK1/2信号通路，并诱导细胞凋亡，同时抑制细胞集落形成[6]。
在体内，在表达FGFR2的OCUM-2MD3胃癌异种移植模型中，口服TAS-120（0.15、0.5、1.5和5mg/kg；每日一次，持续14天）可剂量依赖性地显著抑制肿瘤生长，且治疗期间未出现早期耐药迹象[7]。在FGFR2-KIAA1217融合阳性的人源性异种移植（PDX）模型（MG69）中，口服TAS-120（25mg/kg；每日一次）治疗可导致肿瘤消退和完全增殖抑制，效果在3天内显现并持续14天，同时伴随FGFR下游MEK/ERK和SHP2信号通路的抑制[8]。