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

• Published in: Biochemical and biophysical research communications Vol. 477; no. 4; pp. 937 - 944
• Main Authors: Rastogi, Ichwaku, Rajanna, Supriya, Webb, Andrew, Chhabra, Gagan, Foster, Brad, Webb, Brian, Puri, Neelu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.09.2016
• Subjects: 60 APPLIED LIFE SCIENCES; Antineoplastic Agents - administration & dosage; cadherins; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; cell adhesion; Cell Line, Tumor; CELL PROLIFERATION; DIAGNOSIS; Drug Resistance, Neoplasm; DRUGS; EMT; Epithelial-Mesenchymal Transition - drug effects; epithelium; GENES; Humans; lung neoplasms; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; LUNGS; miR-200a; MOLECULES; MORPHOLOGY; neoplasm cells; NEOPLASMS; NSCLC; PATIENTS; people; Protein Kinase Inhibitors - administration & dosage; protein synthesis; Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Epidermal Growth Factor - metabolism; RECEPTORS; repressor proteins; SENSITIVITY; small interfering RNA; therapeutics; THERAPY; TKI resistance; Treatment Outcome; TYROSINE; vimentin; Zeb-1; β-Catenin; β-Catenin; Zeb-1; TKI resistance; β-Catenin; miR-200a; NSCLC; EMT
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.07.003

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. •Resistance to TKIs in NSCLC cells is mediated via modulation in EMT related proteins.•EMT may induce c-Met mediated TKI resistance, similar to EGFR TKI resistance.•Role of β-catenin and cadherins in TKI resistance was validated by FACS and qPCR.•Knockdown of β-catenin or Zeb-1 can increase TKI sensitivity in TKI-resistant cells.•Targeting key EMT related proteins may overcome TKI resistance in NSCLC.