Antitumour efficacy of MEK inhibitors in human lung cancer cells and their derivatives with acquired resistance to different tyrosine kinase inhibitors.
Br J Cancer
; 105(3): 382-92, 2011 Jul 26.
Article
em En
| MEDLINE
| ID: mdl-21750552
ABSTRACT
BACKGROUND:
To study the molecular mechanisms regulating cancer cell resistance to four different tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, vandetanib and sorafenib.METHODS:
An in vitro model of acquired resistance to these TKIs was developed by continuously treating the human lung adenocarcinoma cell line CALU-3 with escalating doses of each drug. Transcriptional profiling was performed with Agilent whole genome microarrays. Western blot analysis, enzyme-linked immunosorbent (ELISA), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation, migration, invasion and anchorage-independent colony growth assays were conducted in vitro and experiments with established xenografts in athymic nude mice were performed in vivo in parental (P) and TKI-resistant (R) CALU-3 cell lines.RESULTS:
As compared with P-CALU-3 cells, in TKI-R CALU-3 cell lines a significant increase in the expression of activated, phosphorylated MET, IGF-1R, AKT, MEK, MAPK and of survivin was observed. Downregulation of E-cadherin and amphiregulin mRNAs and upregulation of vimentin, VE-cadherin, HIF-1α and vascular endothelial growth factor receptor-1 mRNAs were observed in all four TKI-R CALU-3 cell lines. All four TKI-R CALU-3 cells showed increased invasion, migration and anchorage-independent growth. Together, these data suggest epithelial to mesenchymal transition (EMT) in TKI-R CALU-3 cells. Treatment with several agents that target AKT, MET or IGF-1R did not affect TKI-R CALU-3 cell proliferation. In contrast, treatment with MSC19363669B and selumetinib, two selective MEK inhibitors, caused inhibition of cell proliferation, invasion, migration, anchorage-independent growth in vitro and of tumour growth in vivo of all four TKI-R CALU-3 cell lines.CONCLUSION:
These data suggest that resistance to four different TKIs is characterised by EMT, which is MEK-inhibitor sensitive in human CALU-3 lung adenocarcinoma.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Adenocarcinoma
/
Resistencia a Medicamentos Antineoplásicos
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MAP Quinase Quinase Quinases
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Inibidores de Proteínas Quinases
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Br J Cancer
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Itália