c-Myc Alteration Determines the Therapeutic Response to FGFR Inhibitors
c-Myc Alteration Determines the Therapeutic Response to FGFR Inhibitors
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c-Myc 改变决定 FGFR 抑制剂的治疗反应
DOI：
10.1158/1078-0432.ccr-15-2448
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发表时间：
2017-02-01
影响因子：
11.5
通讯作者：
Geng, Meiyu
中科院分区：
文献类型：
--
作者：
Liu, Hongyan;Ai, Jing;Geng, Meiyu
目的：最近，新出现的证据表明，致癌激酶与特定的下游效应物相关，以控制肿瘤生长，这表明激酶靶向癌症治疗中的潜在翻译价值。酪氨酸激酶FGFR在多种癌症类型中是异常的，是分子靶向癌症治疗中研究最多的激酶之一。在此，我们研究了是否存在汇聚FGFR信号传导并决定FGFR靶向治疗的治疗反应的关键下游效应物。实验设计：使用一系列测定来评估c-Myc在FGFR异常癌症中的作用及其在FGFR靶向治疗中的翻译相关性，包括使用细胞活力测定评估药物敏感性、使用免疫印迹分析进行信号转导分析以及使用基于癌细胞系的异种移植物和患者来源的异种移植物模型进行体内抗肿瘤功效。结果：我们发现c-Myc在FGFR异常的癌症中是先于FGFR-MEK/ERK信号传导的关键下游效应子。c-Myc的破坏压倒了由组成型活性FGFR驱动的细胞增殖。FGFR依赖性癌症中的FGFR抑制通过在苏氨酸58处磷酸化c-Myc促进c-Myc降解。在体外和体内，不可降解的c-Myc突变体的异位表达赋予对FGFR抑制的抗性。c-Myc水平的改变严格决定了对FGFR抑制剂的反应，如FGFR反应性癌症亚组以及对FGFR抑制具有获得性或新生耐药性的癌症中所证明的。结论：这项研究揭示了FGFR依赖性癌症中FGFR与下游效应子c-Myc之间的严格关联，并表明c-Myc在FGFR靶向癌症治疗中的潜在治疗价值。临床癌症研究; 23（4）; 974-84。©2016 AACR版权所有
Purpose: Lately, emerging evidence has suggested that oncogenic kinases are associated with specific downstream effectors to govern tumor growth, suggesting potential translational values in kinase-targeted cancer therapy. Tyrosine kinase FGFR, which is aberrant in various cancer types, is one of the most investigated kinases in molecularly targeted cancer therapy. Herein, we investigated whether there exists key downstream effector(s) that converges FGFR signaling and determines the therapeutic response of FGFR-targeted therapy. Experimental Design: A range of assays was used to assess the role of c-Myc in FGFR aberrant cancers and its translational relevance in FGFR-targeted therapy, including assessment of drug sensitivity using cell viability assay, signaling transduction profiling using immunoblotting, and in vivo antitumor efficacy using cancer cell line–based xenografts and patient-derived xenografts models. Results: We discovered that c-Myc functioned as the key downstream effector that preceded FGFR-MEK/ERK signaling in FGFR aberrant cancer. Disruption of c-Myc overrode the cell proliferation driven by constitutively active FGFR. FGFR inhibition in FGFR-addicted cancer facilitated c-Myc degradation via phosphorylating c-Myc at threonine 58. Ectopic expression of undegradable c-Myc mutant conferred resistance to FGFR inhibition both in vitro and in vivo. c-Myc level alteration stringently determined the response to FGFR inhibitors, as demonstrated in FGFR-responsive cancer subset, as well as cancers bearing acquired or de novo resistance to FGFR inhibition. Conclusions: This study reveals a stringent association between FGFR and the downstream effector c-Myc in FGFR-dependent cancers, and suggests the potential therapeutic value of c-Myc in FGFR-targeted cancer therapy. Clin Cancer Res; 23(4); 974–84. ©2016 AACR.