Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells.
Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells.
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配体相关的 ERBB2/3 激活赋予 FGFR3 依赖性癌细胞对 FGFR 抑制的获得性抵抗。
作者：
成纤维细胞生长因子受体(FGFRs)的躯体改变已在多种恶性肿瘤中被描述。一些抗FGFR疗法目前正在对FGFR基因扩增、突变和易位的受试者进行临床试验。在这里，我们建立了获得性抵抗FGFR抑制的细胞系模型，方法是将携带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ponatinib。我们发现，耐药的获得是快速、可逆的，其特征是上皮细胞向间充质细胞的转变(EMT)以及从依赖FGFR3向ERBB家族成员的转变。获得性耐药性与基因表达的明显变化有关，包括ERBB2/3配体的产生增加，这足以在FGFR3依赖的情况下驱动耐药性，而不是对其他FGFR家族成员的依赖。这些数据支持这样的概念，即ERBB家族成员的激活足以绕过对FGFR3的依赖，并表明当靶向FGFR3依赖的癌症时，同时抑制这两个途径可能是可取的。
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.
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影响因子：
28.2
作者：
Herrera-Abreu MT;Pearson A;Campbell J;Shnyder SD;Knowles MA;Ashworth A;Turner NC
通讯作者：
Turner NC
影响因子：
3.8
作者：
Kim J;Jeong H;Lee Y;Kim C;Kim H;Kim A
通讯作者：
Kim A
影响因子：
20.3
作者：
Chesi, M;Brents, LA;Bergsagel, PL
通讯作者：
Bergsagel, PL
影响因子：
50.3
作者：
Lu J;Guo H;Treekitkarnmongkol W;Li P;Zhang J;Shi B;Ling C;Zhou X;Chen T;Chiao PJ;Feng X;Seewaldt VL;Muller WJ;Sahin A;Hung MC;Yu D
通讯作者：
Yu D
影响因子：
7.5
作者：
Bublil, Erez M.;Yarden, Yosef
通讯作者：
Yarden, Yosef