Nakamura Ikuko Takeda, Kohsaka Shinji, Ikegami Masachika, Ikeuchi Hiroshi, Ueno Toshihide, Li Kunhua, Beyett Tyler S, Koyama Takafumi, Shimizu Toshio, Yamamoto Noboru, Takahashi Fumiyuki, Takahashi Kazuhisa, Eck Michael J, Mano Hiroyuki
Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
Department of Respiratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
NPJ Precis Oncol. 2021 Jul 16;5(1):66. doi: 10.1038/s41698-021-00204-0.
Various genetic alterations of the fibroblast growth factor receptor (FGFR) family have been detected across a wide range of cancers. However, inhibition of FGFR signaling by kinase inhibitors demonstrated limited clinical effectiveness. Herein, we evaluated the transforming activity and sensitivity of 160 nonsynonymous FGFR mutations and ten fusion genes to seven FGFR tyrosine kinase inhibitors (TKI) using the mixed-all-nominated-in-one (MANO) method, a high-throughput functional assay. The oncogenicity of 71 mutants was newly discovered in this study. The FGFR TKIs showed anti-proliferative activities against the wild-type FGFRs and their fusions, while several hotspot mutants were relatively resistant to those TKIs. The drug sensitivities assessed with the MANO method were well concordant with those evaluated using in vitro and in vivo assays. Comprehensive analysis of published FGFR structures revealed a possible mechanism through which oncogenic FGFR mutations reduce sensitivity to TKIs. It was further revealed that recurrent compound mutations within FGFRs affect the transforming potential and TKI-sensitivity of corresponding kinases. In conclusion, our study suggests the importance of selecting suitable inhibitors against individual FGFR variants. Moreover, it reveals the necessity to develop next-generation FGFR inhibitors, which are effective against all oncogenic FGFR variants.
在多种癌症中均检测到成纤维细胞生长因子受体（FGFR）家族的各种基因改变。然而，激酶抑制剂对FGFR信号传导的抑制作用在临床上显示出有限的有效性。在此，我们使用混合全提名一体（MANO）方法（一种高通量功能测定法）评估了160个非同义FGFR突变和10个融合基因对7种FGFR酪氨酸激酶抑制剂（TKI）的转化活性和敏感性。本研究新发现了71个突变体的致癌性。FGFR TKI对野生型FGFR及其融合体显示出抗增殖活性，而一些热点突变体对这些TKI相对耐药。用MANO方法评估的药物敏感性与使用体外和体内试验评估的结果高度一致。对已发表的FGFR结构的综合分析揭示了致癌性FGFR突变降低对TKI敏感性的可能机制。进一步发现，FGFR内的复发性复合突变会影响相应激酶的转化潜力和TKI敏感性。总之，我们的研究表明针对个体FGFR变体选择合适抑制剂的重要性。此外，它揭示了开发对所有致癌性FGFR变体均有效的下一代FGFR抑制剂的必要性。
