IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations

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 enr...

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Main Authors: 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.
Format: Online
Language:English
Published: Nature Publishing Group 2013
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759044/
id pubmed-3759044
recordtype oai_dc
spelling pubmed-37590442013-09-03 IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations 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. Article 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. Nature Publishing Group 2013-09-02 /pmc/articles/PMC3759044/ /pubmed/23994953 http://dx.doi.org/10.1038/srep02560 Text en Copyright © 2013, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
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.
spellingShingle 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.
IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations
author_facet 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.
author_sort Vazquez-Martin, Alejandro
title IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations
title_short IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations
title_full IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations
title_fullStr IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations
title_full_unstemmed IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations
title_sort igf-1r/epithelial-to-mesenchymal transition (emt) crosstalk suppresses the erlotinib-sensitizing effect of egfr exon 19 deletion mutations
description 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.
publisher Nature Publishing Group
publishDate 2013
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759044/
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