Título:
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IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations
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Autor/a:
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Vazquez Martin, Alejandro; Cufí, Sílvia; Oliveras Ferraros, Cristina; Torres Garcia, Violeta Zenobia; Corominas Faja, Bruna; Cuyàs, Elisabet; Bonavia, Rosa; Visa, Joana; Martin Castillo, Begoña; Barrajón Catalán, Enrique; Micol, Vicente; Bosch Barrera, Joaquim; Menendez, Javier A.
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Abstract:
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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 (TGF beta 1)-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 TGF beta 1'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. |
Materia(s):
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-Càncer de pulmó -Lung cancer |
Derechos:
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cc by (c) Vazquez Martin et al., 2013
http://creativecommons.org/licenses/by/3.0/es/ |
Tipo de documento:
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Artículo Artículo - Versión publicada |
Editor:
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Nature Publishing Group
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