A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop.
A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop.
复制标题
DOI：
10.1038/oncsis.2013.4
复制
发表时间：
2013-03-25
期刊：
影响因子：
6.2
通讯作者：
Heasley, L. E.
中科院分区：
文献类型：
--
作者：
Ware, K. E.;Hinz, T. K.;Kleczko, E.;Singleton, K. R.;Marek, L. A.;Helfrich, B. A.;Cummings, C. T.;Graham, D. K.;Astling, D.;Tan, A-C;Heasley, L. E.
尽管表皮生长因子受体(EGFR)成瘾的肺肿瘤最初对EGFR特异性酪氨酸激酶抑制剂(TKIs)、吉非替尼和厄洛替尼有戏剧性反应，但几乎所有肿瘤都出现耐药和复发。为了探索介导获得性耐药的新机制，我们使用了携带EGFR激活突变的非小细胞肺癌(NSCLC)细胞系，并通过组织培养的慢性适应使它们对EGFR特异性TKI产生耐药性。除了先前观察到的包括EGFR-T790M‘Gate-Keeper’突变和MET扩增在内的耐药机制外，包括HCC4006、HCC2279和H1650在内的7个长期适应的NSCLC细胞系中的一组细胞显示出显著的成纤维细胞生长因子(FGF)2和成纤维细胞生长因子受体1(FGFR1)mRNA和蛋白的诱导。此外，通过CDH1、VIM、ZEB1和ZEB2表达的变化以及Matrigel生长特性的改变来评估对EGFR特异性TKIs的适应伴随着上皮向间充质的转变(EMT)。在FGF2和FGFR1表达增加的适应细胞系中，生长和信号的测量，而不是EMT，被FGFR特异性的TKI、成纤维细胞生长因子配体陷阱和RNAi沉默的FGFR1所阻断。在亲代HCC4006细胞中，Gefitinib强烈抑制细胞生长，尽管耐药克隆在10天内出现进展。联合使用Gefitinib和AZD4547(一种FGFR特异性TKI)可以防止耐药克隆的生长。因此，在慢性适应EGFR特异性TKI后，FGF2和FGFR1的诱导在最初对EGFR特异性TKI敏感的肺癌细胞系中提供了一种新的自分泌受体酪氨酸激酶驱动的旁路通路。这些发现支持FGFR特异性TKIs作为现有靶向治疗策略的潜在有价值的补充，使用EGFR特异性TKI来预防或延迟EGFR驱动的非小细胞肺癌的获得性耐药性。
Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M ‘gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC.
登录
查看更多内容
影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
3.5
作者：
McDermott, LA;Simcox, M;Luk, KC
通讯作者：
Luk, KC
DOI：
10.1073/pnas.0710370104
发表时间：
2007-12-26
影响因子：
11.1
作者：
Bean, James;Brennan, Cameron;Pao, William
通讯作者：
Pao, William
影响因子：
7.3
作者：
Cui, J. Jean;Tran-Dube, Michelle;Edwards, Martin P.
通讯作者：
Edwards, Martin P.
影响因子：
64.5
作者：
Glickman MS;Sawyers CL
通讯作者：
Sawyers CL