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Oncogene DOI:10.1038/onc.2014.161

Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells.

Publication TypeJournal Article
Year of Publication2015
AuthorsWang, J, Mikse, O, Liao, RG, Li, Y, Tan, L, Janne, PA, Gray, NS, Wong, K-k, Hammerman, PS
JournalOncogene
Volume34
Issue17
Pages2167-77
Date Published2015 Apr 23
ISSN1476-5594
KeywordsCell Line, Tumor, Drug Resistance, Neoplasm, Enzyme Activation, Epithelial-Mesenchymal Transition, Humans, Imidazoles, Phenylurea Compounds, Protein Kinase Inhibitors, Pyridazines, Pyrimidines, Receptor, ErbB-2, Receptor, ErbB-3, Receptor, Fibroblast Growth Factor, Type 3
Abstract

Somatic alterations of fibroblast growth factor receptors (FGFRs) have been described in a wide range of malignancies. A number of anti-FGFR therapies are currently under investigation in clinical trials for subjects with FGFR gene amplifications, mutations and translocations. Here, we develop cell line models of acquired resistance to FGFR inhibition by exposure of cell lines harboring FGFR3 gene amplification and translocation to the selective FGFR inhibitor BGJ398 and multitargeted FGFR inhibitor ponatinib. We show that the acquisition of resistance is rapid, reversible and characterized by an epithelial to mesenchymal transition and a switch from dependency on FGFR3 to ERBB family members. Acquired resistance was associated with demonstrable changes in gene expression including increased production of ERBB2/3 ligands, which were sufficient to drive resistance in the setting of FGFR3 dependency but not dependency on other FGFR family members. These data support the concept that activation of ERBB family members is sufficient to bypass dependency on FGFR3 and suggest that concurrent inhibition of these two pathways may be desirable when targeting FGFR3-dependent cancers.

URLhttp://dx.doi.org/10.1038/onc.2014.161
DOI10.1038/onc.2014.161
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24909170?dopt=Abstract

Alternate JournalOncogene
PubMed ID24909170
PubMed Central IDPMC4261066
Grant ListK08 CA163677 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
R01 CA140594 / CA / NCI NIH HHS / United States