title: IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations.
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 (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.
authors.affiliation: Metabolism & Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vazquez-Martin
authors.forename: Sílvia
authors.initials: S
authors.lastname: Cufí
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliveras-Ferraros
authors.forename: Violeta Zenobia
authors.initials: VZ
authors.lastname: Torres-Garcia
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.forename: Rosa
authors.initials: R
authors.lastname: Bonavia
authors.forename: Joana
authors.initials: J
authors.lastname: Visa
authors.forename: Begoña
authors.initials: B
authors.lastname: Martin-Castillo
authors.forename: Enrique
authors.initials: E
authors.lastname: Barrajón-Catalán
authors.forename: Vicente
authors.initials: V
authors.lastname: Micol
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bosch-Barrera
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D000069347:Erlotinib Hydrochloride; D005091:Exons / Q000235:genetics; D018773:Genes, erbB-1 / Q000235:genetics*; D006801:Humans; D011799:Quinazolines / Q000008:administration & dosage*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D017526:Receptor, IGF Type 1