Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer.
Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer.
复制标题
DOI：
10.1038/s41598-023-46586-y
复制
发表时间：
2023-11-18
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
在乳腺癌中发现了成纤维细胞生长因子受体（FGFR）基因的几种变化;然而，它们尚未被很好地描述为治疗靶点。Futibatinib（TAS-120; Taiho）是一种新型的选择性泛FGFR抑制剂，可在纳摩尔浓度下抑制FGFR 1 -4。我们试图确定futibatinib在乳腺癌模型中的疗效。用futibatinib治疗具有各种FGFR 1 -4改变和表达水平的9个乳腺癌患者来源的异种移植物（PDX）。通过肿瘤体积和肿瘤倍增时间的变化评价抗肿瘤疗效。在体外进一步表征了表明体内对futibatinib致敏的变化。患者肿瘤和匹配的PDX之间的FGFR基因表达显著相关;然而，总体PDX具有更高的FGFR 3 -4表达。Futibatinib抑制了9例PDX中3例的肿瘤生长，在FGFR 2扩增模型中肿瘤稳定，在FGFR 2 Y375 C突变/扩增模型中肿瘤消退时间延长（> 110天）。MCF 10A细胞中FGFR 2过表达和FGFR 2 Y375 C表达在更大程度上增强了细胞生长和对futibatinib的敏感性。根据机构和公共数据库，乳腺癌患者中FGFR 2突变和扩增的群体频率分别为1.1%-2.6%和1.5%-2.5%。乳腺癌中的FGFR 2改变可能是futibatinib的罕见但非常有希望的靶点。
Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib’s efficacy in breast cancer models. Nine breast cancer patient–derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2-amplified model and prolonged regression (> 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%–2.6% and 1.5%–2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1038/nrm3528
发表时间：
2013-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
宇宙（癌症中的体细胞突变目录）数据库和网站。
影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
11.2
作者：
Dey, Julien H.;Bianchi, Fabrizio;Hynes, Nancy E.
通讯作者：
Hynes, Nancy E.
影响因子：
6.4
作者：
Gruenewald, Sylvia;Politz, Oliver;Ziegelbauer, Karl
通讯作者：
Ziegelbauer, Karl