title: Mechanism of c-Met and EGFR tyrosine kinase inhibitor resistance through epithelial mesenchymal transition in non-small cell lung cancer.
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.
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Illinois, United States.
authors.forename: Ichwaku
authors.initials: I
authors.lastname: Rastogi
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Illinois, United States.
authors.forename: Supriya
authors.initials: S
authors.lastname: Rajanna
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Illinois, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Webb
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Illinois, United States.
authors.forename: Gagan
authors.initials: G
authors.lastname: Chhabra
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Illinois, United States.
authors.forename: Brad
authors.initials: B
authors.lastname: Foster
authors.affiliation: Thermo Fisher Scientific, Rockford, Illinois, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Webb
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Illinois, United States. Electronic address: neelupur@uic.edu.
authors.forename: Neelu
authors.initials: N
authors.lastname: Puri
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: EMT; NSCLC; TKI resistance; Zeb-1; miR-200a; β-Catenin