PMID- 23994953
OWN - NLM
STAT- MEDLINE
DCOM- 20140214
LR  - 20220409
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 3
DP  - 2013
TI  - IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the 
      erlotinib-sensitizing effect of EGFR exon 19 deletion mutations.
PG  - 2560
LID - 10.1038/srep02560 [doi]
LID - 2560
AB  - 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 
      (TGFbeta1)-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 TGFbeta1'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.
FAU - Vazquez-Martin, Alejandro
AU  - Vazquez-Martin A
AD  - Metabolism & Cancer Group, Translational Research Laboratory, Catalan Institute 
      of Oncology, Girona, Catalonia, Spain.
FAU - Cufi, Silvia
AU  - Cufi S
FAU - Oliveras-Ferraros, Cristina
AU  - Oliveras-Ferraros C
FAU - Torres-Garcia, Violeta Zenobia
AU  - Torres-Garcia VZ
FAU - Corominas-Faja, Bruna
AU  - Corominas-Faja B
FAU - Cuyas, Elisabet
AU  - Cuyas E
FAU - Bonavia, Rosa
AU  - Bonavia R
FAU - Visa, Joana
AU  - Visa J
FAU - Martin-Castillo, Begona
AU  - Martin-Castillo B
FAU - Barrajon-Catalan, Enrique
AU  - Barrajon-Catalan E
FAU - Micol, Vicente
AU  - Micol V
FAU - Bosch-Barrera, Joaquim
AU  - Bosch-Barrera J
FAU - Menendez, Javier A
AU  - Menendez JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Quinazolines)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
SB  - IM
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/pathology/*physiopathology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - Epithelial-Mesenchymal Transition/drug effects/*physiology
MH  - Erlotinib Hydrochloride
MH  - Exons/genetics
MH  - Genes, erbB-1/*genetics
MH  - Humans
MH  - Quinazolines/*administration & dosage
MH  - Receptor, IGF Type 1/*metabolism
MH  - Sequence Deletion/*genetics
MH  - Treatment Outcome
PMC - PMC3759044
COIS- AstraZeneca (Spain) provided partial financial support for the present study via 
      an educational grant to J.A.M. and J.B.-B.
EDAT- 2013/09/03 06:00
MHDA- 2014/02/15 06:00
PMCR- 2013/09/02
CRDT- 2013/09/03 06:00
PHST- 2013/03/14 00:00 [received]
PHST- 2013/07/31 00:00 [accepted]
PHST- 2013/09/03 06:00 [entrez]
PHST- 2013/09/03 06:00 [pubmed]
PHST- 2014/02/15 06:00 [medline]
PHST- 2013/09/02 00:00 [pmc-release]
AID - srep02560 [pii]
AID - 10.1038/srep02560 [doi]
PST - ppublish
SO  - Sci Rep. 2013;3:2560. doi: 10.1038/srep02560.