Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.
Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.
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DOI：
10.1038/oncsis.2016.48
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发表时间：
2016-07-18
期刊：
影响因子：
6.2
通讯作者：
Cho BC
中科院分区：
文献类型：
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作者：
Kim SM;Kim H;Yun MR;Kang HN;Pyo KH;Park HJ;Lee JM;Choi HM;Ellinghaus P;Ocker M;Paik S;Kim HR;Cho BC
异常的成纤维细胞生长因子受体（FGFR）激活/表达是肺癌（LC）的共同特征。在这项研究中，我们评估了LC细胞系对两种有效的选择性FGFR抑制剂AZD4547和BAY116387的抗肿瘤活性及其获得性耐药机制。AZD4547和BAY1163877的抗肿瘤活性在24个LC细胞系中进行了筛选，其中5个细胞系有FGFR1扩增。两种含有FGFR1扩增的细胞系H1581和DMS114对FGFR抑制剂敏感（IC50<250 nm）。建立了fgfr1扩增的抗AZD4547或BAY116387的H1581细胞克隆（分别为H1581AR和H1581BR细胞）。受体酪氨酸激酶（RTK）阵列和免疫印迹分析显示，与亲本细胞相比，Met在H1581AR/BR细胞中有较强的过表达和活化。基于京都基因与基因组百科（KEGG）数据库的基因集富集分析显示，H1581AR/BR细胞中细胞因子-细胞因子受体相互作用通路显著富集，其中Met对核心富集有显著贡献。基因组DNA定量PCR和荧光原位杂交分析显示，MET在H1581AR细胞中扩增，而在H1581BR细胞中没有扩增。Met扩增通过激活ErbB3驱动H1581AR细胞对AZD4547的获得性耐药。FGFR抑制剂和间变性淋巴瘤激酶(ALK)/Met抑制剂、克唑替尼或Met特异性短干扰RNA （siRNA）联合治疗可协同抑制H1581AR和H1581BR细胞的细胞增殖。相反，Met在H1581细胞中的异位表达使其对AZD4547和BAY1163877产生抗性。对FGFR抑制剂的获得性耐药不仅改变了细胞形态，还通过诱导上皮细胞向间质细胞的转化，促进了耐药克隆的迁移和侵袭。综上所述，我们的数据表明Met激活足以绕过对FGFR信号的依赖。当靶向FGFR依赖性LC时，同时抑制Met和FGFR通路可能具有协同的临床益处。
Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50<250 nm). Clones of FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine–cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent inhibition of the Met and FGFR pathways may have synergistic clinical benefits when targeting FGFR-dependent LC.