IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations.
IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations.
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DOI：
10.1038/srep02560
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发表时间：
2013
影响因子：
4.6
通讯作者：
Menendez, Javier A.
中科院分区：
文献类型：
--
作者：
Vazquez-Martin, Alejandro;Cufi, Silvia;Oliveras-Ferraros, Cristina;Zenobia Torres-Garcia, Violeta;Corominas-Faja, Bruna;Cuyas, Elisabet;Bonavia, Rosa;Visa, Joana;Martin-Castillo, Begona;Barrajon-Catalan, Enrique;Micol, Vicente;Bosch-Barrera, Joaquim;Menendez, Javier A.
利用携带埃洛替尼敏感型表皮生长因子受体(EGFR)外显子19突变delE746-A750的非小细胞肺癌(NSCLC)细胞，我们开发了埃洛替尼耐药衍生物，其中高活性的胰岛素样生长因子-1受体(IGF-1R)信号与丰富的上皮向间充质转化(EMT)相关的形态和转录特征有关。然后，我们探讨了在没有第二位点EGFR突变、MET和Ax1过度激活的情况下，IGF-1R/EMT串扰是否足以促进厄洛替尼的难治性。在药物敏感的delE746-A750β突变存在的情况下，转化生长因子-β1(TGFEGFR 1)诱导的间质转分化足以阻碍厄洛替尼的功能。药物阻断胰岛素样生长因子-1R可完全阻止转化生长因子钙粘蛋白1‘S激活β蛋白信号的能力[E-钙粘蛋白低/波形蛋白高]。单独使用厄洛替尼能够在delE746-A750突变的上皮细胞中快速激活IGF-1R依赖的、波形蛋白丰富的间充质样表型。即使是暂时的，NSCLC细胞固有的可塑性经历IGF-1R和EMT信号通路之间的串扰可以充分消除高度流行的EGFR突变对厄洛替尼的增敏作用，并表明迫切需要双重IGF-1R/EMT靶向策略来规避厄洛替尼耐药性。
Using non-small cell lung carcinoma (NSCLC) cells harboring the erlotinib-sensitizing Epidermal Growth Factor Receptor (EGFR) exon 19 mutation delE746-A750, we developed erlotinib-refractory derivatives in which hyperactive Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling associated with enrichment in epithelial-to-mesenchymal transition (EMT)-related morphological and transcriptional features. We then explored whether an IGF-1R/EMT crosstalk was sufficient to promote erlotinib refractoriness in the absence of second-site EGFR mutations, MET and AXL hyperactivation. Transforming Growth Factor-beta1 (TGFβ1)-induced mesenchymal trans-differentiation was sufficient to impede erlotinib functioning in the presence of drug-sensitive delE746-A750 EGFR mutation. Pharmacological blockade of IGF-1R fully prevented the TGFβ1's ability to activate an EMT protein signature [E-cadherin low/vimentin high]. The sole presence of erlotinib was capable of rapidly activate an IGF-1R-dependent, vimentin-enriched mesenchymal-like phenotype in delE746-A750-mutated epithelial cells. Even if transient, NSCLC cells' intrinsic plasticity to undergo crosstalk between IGF-1R and EMT signaling pathways can sufficiently eliminate the erlotinib-sensitizing effect of highly prevalent EGFR mutations and suggests the urgent need for dual IGF-1R/EMT-targeting strategies to circumvent erlotinib resistance.
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影响因子：
8.8
作者：
Bryant, J. L.;Britson, J.;Balko, J. M.;Willian, M.;Timmons, R.;Frolov, A.;Black, E. P.
通讯作者：
Black, E. P.
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
5.3
作者：
Kajita, M;McClinic, KN;Wade, PA
通讯作者：
Wade, PA
DOI：
10.1073/pnas.0502860102
发表时间：
2005-05-24
影响因子：
11.1
作者：
Kwak, EL;Sordella, R;Haber, DA
通讯作者：
Haber, DA
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B