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.
journal_name
Oncogenejournal_title
Oncogeneauthors
Wang J,Mikse O,Liao RG,Li Y,Tan L,Janne PA,Gray NS,Wong KK,Hammerman PSdoi
10.1038/onc.2014.161subject
Has Abstractpub_date
2015-04-23 00:00:00pages
2167-77issue
17eissn
0950-9232issn
1476-5594pii
onc2014161journal_volume
34pub_type
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