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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	4	2017 Feb 15	974-984	Clin Cancer Res

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

Gene	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 FGFR2 over exp	stomach cancer	sensitive	Fexagratinib	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	colon cancer	sensitive	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) reduced Myc expression, induced cell-cycle arrest, and inhibited growth of a colon cancer cell line with FGFR2 amplification in culture (PMID: 27401245).	27401245
FGFR2 amp FGFR2 over exp	stomach cancer	sensitive	Infigratinib	Preclinical - Pdx	Actionable	In a preclinical study, Truseltiq (infigratinib) 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	Fexagratinib	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
FGFR3 amp	urinary system cancer	sensitive	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) 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
FGFR3 S249C	urinary system cancer	sensitive	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) 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	Fexagratinib	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