ASP5878, a selective FGFR inhibitor, to treat FGFR3-dependent urothelial cancer with or without chemoresistance.
ASP5878, a selective FGFR inhibitor, to treat FGFR3-dependent urothelial cancer with or without chemoresistance.
复制标题
ASP5878 是一种选择性 FGFR 抑制剂，用于治疗具有或不具有化疗耐药性的 FGFR3 依赖性尿路上皮癌。
DOI：
10.1111/cas.13124
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发表时间：
2017-02
期刊：
影响因子：
5.7
通讯作者：
Kuromitsu S
中科院分区：
文献类型：
--
作者：
Kikuchi A;Suzuki T;Nakazawa T;Iizuka M;Nakayama A;Ozawa T;Kameda M;Shindoh N;Terasaka T;Hirano M;Kuromitsu S
FGF/FGFR基因畸变如扩增、突变和融合与许多类型的人类癌症有关，包括尿路上皮癌。FGFR激酶抑制剂有望成为携带FGFR3基因改变的尿路上皮癌的靶向治疗方法。ASP5878是一种临床研究中的FGFR1、2、3和4的选择性抑制剂，可选择性抑制23种尿路上皮癌细胞系中携带FGFR3点突变或融合（UM‐UC‐14、RT‐112、RT4和SW 780）的细胞增殖。此外，ASP5878抑制了MDR1过表达的阿霉素耐药UM‐UC‐14细胞系和吉西他滨耐药RT‐112细胞系的细胞增殖。在耐吉西他滨的RT - 112细胞系中，癌蛋白c - MYC的表达高于亲本RT - 112细胞系，ASP5878降低了亲本RT - 112和耐吉西他滨的RT - 112细胞系中c - MYC的表达。在UM‐UC‐14、RT‐112和耐吉西他滨RT‐112异种移植瘤模型中，每日口服一次ASP5878显示出有效的抗肿瘤活性，且不影响体重。这些研究结果表明，ASP5878有潜力成为口服靶向治疗在获得吉西他滨或阿霉素耐药后携带FGFR3融合或FGFR3点突变的尿路上皮癌。
FGF/FGFR gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers including urothelial cancer. FGFR kinase inhibitors are expected to be a targeted therapy for urothelial cancer harboring FGFR3 gene alternations. ASP5878, a selective inhibitor of FGFR1, 2, 3 and 4 under clinical investigation, selectively inhibited cell proliferation of urothelial cancer cell lines harboring FGFR3 point mutation or fusion (UM‐UC‐14, RT‐112, RT4 and SW 780) among 23 urothelial cancer cell lines. Furthermore, ASP5878 inhibited cell proliferation of adriamycin‐resistant UM‐UC‐14 cell line harboring MDR1 overexpression and gemcitabine‐resistant RT‐112 cell line. The protein expression of c‐MYC, an oncoprotein, in gemcitabine‐resistant RT‐112 cell line was higher than that in RT‐112 parental cell line and ASP5878 decreased the c‐MYC expression in both RT‐112 parental and gemcitabine‐resistant RT‐112 cell lines. Once‐daily oral administration of ASP5878 exerted potent antitumor activities in UM‐UC‐14, RT‐112 and gemcitabine‐resistant RT‐112 xenograft models without affecting body weight. These findings suggest that ASP5878 has the potential to be an oral targeted therapy against urothelial cancer harboring FGFR3 fusion or FGFR3 point mutation after the acquisition of gemcitabine‐ or adriamycin‐resistance.