title: c-Myc Alteration Determines the Therapeutic Response to FGFR Inhibitors.
abstract: 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, andin vivoantitumor 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 bothin vitroandin vivoc-Myc level alteration stringently determined the response to FGFR inhibitors, as demonstrated in FGFR-responsive cancer subset, as well as cancers bearing acquired orde novoresistance 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.
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Shen
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Peng
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China. mygeng@simm.ac.cn jding@simm.ac.cn mhuang@simm.ac.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China. mygeng@simm.ac.cn jding@simm.ac.cn mhuang@simm.ac.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China. mygeng@simm.ac.cn jding@simm.ac.cn mhuang@simm.ac.cn.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051496:Receptor, Fibroblast Growth Factor, Type 1