Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer.
Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer.
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DOI：
10.1038/s41698-021-00204-0
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发表时间：
2021-07-16
影响因子：
7.9
通讯作者：
Mano H
中科院分区：
文献类型：
--
作者：
Nakamura IT;Kohsaka S;Ikegami M;Ikeuchi H;Ueno T;Li K;Beyett TS;Koyama T;Shimizu T;Yamamoto N;Takahashi F;Takahashi K;Eck MJ;Mano H
成纤维细胞生长因子受体（FGFR）家族的各种遗传改变已经在广泛的癌症中被检测到。然而，激酶抑制剂抑制FGFR信号传导的临床效果有限。在此，我们使用一种高通量功能分析方法——混合-所有命名-一体化（MANO）方法，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 TKIs对野生型FGFR及其融合体表现出抗增殖活性，而一些热点突变体对这些TKIs具有相对抗性。用MANO方法评估的药物敏感性与体外和体内试验评估的药物敏感性非常一致。对已发表的FGFR结构的综合分析揭示了致癌FGFR突变降低对TKIs敏感性的可能机制。研究进一步揭示，fgfr中复发性化合物突变影响相应激酶的转化潜能和tki敏感性。总之，我们的研究表明选择合适的抑制剂来对抗单个FGFR变异的重要性。此外，它揭示了开发下一代FGFR抑制剂的必要性，这些抑制剂对所有致癌的FGFR变体都有效。
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.
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影响因子：
64.8
作者：
Hyman DM;Piha-Paul SA;Won H;Rodon J;Saura C;Shapiro GI;Juric D;Quinn DI;Moreno V;Doger B;Mayer IA;Boni V;Calvo E;Loi S;Lockhart AC;Erinjeri JP;Scaltriti M;Ulaner GA;Patel J;Tang J;Beer H;Selcuklu SD;Hanrahan AJ;Bouvier N;Melcer M;Murali R;Schram AM;Smyth LM;Jhaveri K;Li BT;Drilon A;Harding JJ;Iyer G;Taylor BS;Berger MF;Cutler RE Jr;Xu F;Butturini A;Eli LD;Mann G;Farrell C;Lalani AS;Bryce RP;Arteaga CL;Meric-Bernstam F;Baselga J;Solit DB
通讯作者：
Solit DB
影响因子：
64.5
作者：
Bae JH;Lew ED;Yuzawa S;Tomé F;Lax I;Schlessinger J
通讯作者：
Schlessinger J
影响因子：
7.2
作者：
Belov AA;Mohammadi M
通讯作者：
Mohammadi M
影响因子：
1.2
作者：
Alvarez, Angel;Barisone, Gustavo A.;Diaz, Elva
通讯作者：
Diaz, Elva
DOI：
10.1016/s1470-2045(20)30109-1
发表时间：
2020-05
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Abou-Alfa GK;Sahai V;Hollebecque A;Vaccaro G;Melisi D;Al-Rajabi R;Paulson AS;Borad MJ;Gallinson D;Murphy AG;Oh DY;Dotan E;Catenacci DV;Van Cutsem E;Ji T;Lihou CF;Zhen H;Féliz L;Vogel A
通讯作者：
Vogel A