Reference Detail

Ref Type Journal Article
PMID (27401245)
Authors Liu H, Ai J, Shen A, Chen Y, Wang X, Peng X, Chen H, Shen Y, Huang M, Ding J, Geng M
Title c-Myc Alteration Determines the Therapeutic Response to FGFR Inhibitors.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 4
Date 2017 Feb 15
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 amp colon cancer sensitive BGJ398 Preclinical - Cell culture Actionable In a preclinical study, BGJ398 reduced Myc expression, induced cell-cycle arrest, and inhibited growth of a colon cancer cell line with FGFR2 amplification in culture (PMID: 27401245). 27401245
FGFR3 amp urinary system cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 decreased Myc expression, induced cell cycle arrest, and inhibited growth of a urinary tract cancer cell line harboring FGFR3 amplification in culture (PMID: 27401245). 27401245
ETV6-FGFR4 Advanced Solid Tumor sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, treatment with AZD4547 decreased Myc expression and inhibited growth of transformed cells expressing ETV6-FGFR4 (TEL-FGFR4) in culture (PMID: 27401245). 27401245
ETV6-FGFR3 Advanced Solid Tumor sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, treatment with AZD4547 decreased Myc expression and inhibited growth of transformed cells expressing ETV6-FGFR3 (TEL-FGFR3) in culture (PMID: 27401245). 27401245
FGFR3 S249C urinary system cancer sensitive BGJ398 Preclinical - Cell culture Actionable In a preclinical study, BGJ398 decreased Myc expression, induced cell cycle arrest, and inhibited growth of a urinary tract cancer cell line harboring FGFR3 S249C in culture (PMID: 27401245). 27401245
FGFR3 S249C urinary system cancer sensitive AZD4547 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD4547 decreased Myc expression and inhibited growth of a urinary tract cancer cell line harboring FGFR3 S249C in culture and in xenograft models (PMID: 27401245). 27401245
ETV6-FGFR1 Advanced Solid Tumor sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, treatment with AZD4547 decreased Myc expression and inhibited growth of transformed cells expressing ETV6-FGFR1 (TEL-FGFR1) in culture (PMID: 27401245). 27401245
FGFR2 amp FGFR2 over exp stomach cancer sensitive AZD4547 Preclinical - Pdx Actionable In a preclinical study, AZD4547 decreased Myc expression and inhibited tumor growth in patient-derived xenograft (PDX) models of gastric cancer with FGFR2 amplification and over expression (PMID: 27401245). 27401245
FGFR2 amp FGFR2 over exp stomach cancer sensitive BGJ398 Preclinical - Pdx Actionable In a preclinical study, BGJ398 decreased Myc expression and inhibited tumor growth in patient-derived xenograft (PDX) models of gastric cancer with FGFR2 amplification and over expression (PMID: 27401245). 27401245
FGFR3 amp urinary system cancer sensitive BGJ398 Preclinical - Cell culture Actionable In a preclinical study, BGJ398 decreased Myc expression, induced cell cycle arrest, and inhibited growth of a urinary tract cancer cell line harboring FGFR3 amplification in culture (PMID: 27401245). 27401245