Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells
| Autor: | Oliver Mikse, Rachel G. Liao, Nathanael S. Gray, Li Tan, Yvonne Y. Li, Peter S. Hammerman, Kwok-Kin Wong, Jun Wang, Pasi A. Jänne |
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| Rok vydání: | 2014 |
| Předmět: |
musculoskeletal diseases
Cancer Research Epithelial-Mesenchymal Transition animal structures Receptor ErbB-3 Receptor ErbB-2 FGFR Inhibition Biology Molecular oncology Article chemistry.chemical_compound Growth factor receptor Cell Line Tumor Genetics Humans Receptor Fibroblast Growth Factor Type 3 FGFR inhibitors Epithelial–mesenchymal transition Protein Kinase Inhibitors Molecular Biology FGFR3 translocation cancer genomics Phenylurea Compounds acquired resistance Ponatinib Imidazoles Cell cycle Molecular biology Enzyme Activation Pyridazines Pyrimidines chemistry Drug Resistance Neoplasm Fibroblast growth factor receptor embryonic structures Cancer cell Cancer research |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2014.161 |
| Popis: | 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 multi-targeted FGFR inhibitor ponatinib. We show that the acquisition of resistance is rapid, reversible and characterized by an epithelial to mesenchymal transition (EMT) 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. |
| Databáze: | OpenAIRE |
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