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https://hdl.handle.net/2445/126441
Title: | IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations |
Author: | 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. |
Keywords: | Càncer de pulmó Lung cancer |
Issue Date: | 2-Sep-2013 |
Publisher: | Nature Publishing Group |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/srep02560 |
It is part of: | Scientific Reports, 2013, vol. 3 |
URI: | https://hdl.handle.net/2445/126441 |
Related resource: | https://doi.org/10.1038/srep02560 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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