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Biochem Biophys Res Commun. 2016 Sep 2;477(4):937-944. doi: 10.1016/j.bbrc.2016.07.003. Epub 2016 Jul 7.

Mechanism of c-Met and EGFR tyrosine kinase inhibitor resistance through epithelial mesenchymal transition in non-small cell lung cancer.

Author information

1
Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Illinois, United States.
2
Thermo Fisher Scientific, Rockford, Illinois, United States.
3
Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Illinois, United States. Electronic address: neelupur@uic.edu.

Abstract

According to currently available estimates from Cancer Research UK, 14.1 million new lung cancer cases were diagnosed and a staggering 8.2 million people worldwide died from lung cancer in 2012. EGFR and c-Met are two tyrosine kinase receptors most commonly overexpressed or mutated in Non-small Cell Lung Cancer (NSCLC) resulting in increased proliferation and survival of lung cancer cells. Tyrosine kinase inhibitors (TKIs), such as erlotinib, approved by the FDA as first/second line therapy for NSCLC patients have limited clinical efficacy due to acquired resistance. In this manuscript, we investigate and discuss the role of epithelial mesenchymal transition (EMT) in the development of resistance against EGFR and c-Met TKIs in NSCLC. Our findings show that Zeb-1, a transcriptional repressor of E-Cadherin, is upregulated in TKI-resistant cells causing EMT. We observed that TKI-resistant cells have increased gene and protein expression of EMT related proteins such as Vimentin, N-Cadherin, β-Catenin and Zeb-1, while expression of E-Cadherin, an important cell adhesion molecule, was suppressed. We also confirmed that TKI-resistant cells display mesenchymal cell type morphology, and have upregulation of β-Catenin which may regulate expression of Zeb-1, a transcriptional repressor of E-Cadherin in TKI-resistant NSCLC cells. Finally, we show that down-regulating Zeb-1 by inducing miR-200a or β-Catenin siRNA can increase drug sensitivity of TKI-resistant cells.

KEYWORDS:

EMT; NSCLC; TKI resistance; Zeb-1; miR-200a; β-Catenin

PMID:
27396618
PMCID:
PMC4967022
DOI:
10.1016/j.bbrc.2016.07.003
[Indexed for MEDLINE]
Free PMC Article

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