Wang J, Mikse O, Liao R G, Li Y, Tan L, Janne P A, Gray N S, Wong K-k, Hammerman P S
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Oncogene. 2015 Apr 23;34(17):2167-77. doi: 10.1038/onc.2014.161. Epub 2014 Jun 9.
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.
成纤维细胞生长因子受体（FGFRs）的体细胞改变在多种恶性肿瘤中均有报道。目前，一些抗FGFR疗法正在针对患有FGFR基因扩增、突变和易位的受试者进行临床试验研究。在此，我们通过将携带FGFR3基因扩增和易位的细胞系暴露于选择性FGFR抑制剂BGJ398和多靶点FGFR抑制剂波纳替尼，建立了对FGFR抑制产生获得性耐药的细胞系模型。我们发现，耐药的获得迅速且可逆，其特征为上皮-间质转化以及从依赖FGFR3转变为依赖ERBB家族成员。获得性耐药与基因表达的明显变化有关，包括ERBB2/3配体产生增加，这足以在FGFR3依赖的情况下驱动耐药，但在依赖其他FGFR家族成员的情况下则不然。这些数据支持ERBB家族成员的激活足以绕过对FGFR3的依赖这一概念，并表明在靶向FGFR3依赖性癌症时，同时抑制这两条途径可能是可取的。
