title: Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells.
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.
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Integrative Medicine and Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: O
authors.initials: O
authors.lastname: Mikse
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Liao
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Tan
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Belfer Institute of Applied Cancer Sciences, Boston, MA, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Janne
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Belfer Institute of Applied Cancer Sciences, Boston, MA, USA.
authors.forename: K-k
authors.initials: KK
authors.lastname: Wong
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Hammerman
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D051498:Receptor, Fibroblast Growth Factor, Type 3; C545373:ponatinib; C568950:infigratinib; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C496365:FGFR3 protein, human