FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition.
FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition.
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DOI：
10.18632/oncotarget.13117
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发表时间：
2016-12-13
期刊：
影响因子：
--
通讯作者：
Wendt MK
中科院分区：
文献类型：
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作者：
Brown WS;Akhand SS;Wendt MK
肿瘤耐药性的一个新特征是诱导上皮-间质转化（EMT）。然而，EMT介导的耐药机制仍然不清楚。因此，我们用EGFR/Her 2激酶抑制剂拉帕替尼或TGF-β（一种已知的EMT生理诱导剂）对人表皮生长因子受体-2（Her 2）转化的乳腺癌细胞进行了长期治疗。这两种治疗方案均导致稳健的EMT表型，但在停药后，TGF-β诱导的细胞亚群容易经历间充质-上皮转变，而拉帕替尼诱导的细胞未能重建上皮群体。在随后的拉帕替尼治疗期间，在TGF-β刺激和戒断后保留的间充质群体被迅速选择，表现为固有的耐药性。Nanostring癌症进展基因小组揭示了成纤维细胞生长因子受体1（FGFR 1）及其同源配体FGF 2在获得性和固有耐药性中的显着上调。从机制上讲，FGF：Erk 1/2信号传导的功能是稳定EMT转录因子Twist，从而维持间充质和耐药表型。最后，拉帕替尼抗性细胞可以使用最近表征的FGFR共价抑制剂容易地消除。总的来说，我们的数据表明，下一代FGFR靶向治疗可以与Her 2靶向治疗联合使用，以克服这种乳腺癌亚型的耐药性。
An emerging characteristic of drug resistance in cancer is the induction of epithelial-mesenchymal transition (EMT). However, the mechanisms of EMT-mediated drug resistance remain poorly defined. Therefore, we conducted long-term treatments of human epidermal growth factor receptor-2 (Her2)-transformed breast cancer cells with either the EGFR/Her2 kinase inhibitor, Lapatinib or TGF-β, a known physiological inducer of EMT. Both of these treatment regimes resulted in robust EMT phenotypes, but upon withdrawal a subpopulation of TGF-β induced cells readily underwent mesenchymal-epithelial transition, where as Lapatinib-induced cells failed to reestablish an epithelial population. The mesenchymal population that remained following TGF-β stimulation and withdrawal was quickly selected for during subsequent Lapatinib treatment, manifesting in inherent drug resistance. The Nanostring cancer progression gene panel revealed a dramatic upregulation of fibroblast growth factor receptor 1 (FGFR1) and its cognate ligand FGF2 in both acquired and inherent resistance. Mechanistically, FGF:Erk1/2 signaling functions to stabilize the EMT transcription factor Twist and thus maintain the mesenchymal and drug resistant phenotype. Finally, Lapatinib resistant cells could be readily eliminated using recently characterized covalent inhibitors of FGFR. Overall our data demonstrate that next-generation targeting of FGFR can be used in combination with Her2-targeted therapies to overcome resistance in this breast cancer subtype.