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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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/ |
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Open Access Journal |
institution_category |
Foreign Institution |
institution |
US National Center for Biotechnology Information |
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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/ |
_version_ |
1612007437866369024 |