Journal Article

Reverse epithelial-mesenchymal transition contributes to the regain of drug sensitivity in tyrosine kinase inhibitor-resistant non-small cell lung cancer cells

Chen, Chao-Ju, Chen, Man-Chin, Yang, Chih-Jen, Liu, Yu-Peng, Huang, Ming-Shyang, Lee, An-Fu

2017

Overview

Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amplification / Antineoplastic Agents - pharmacology / Biology and Life Sciences / Biotechnology / Blockage / c-Met protein / Cancer / Cell culture / Cell Line, Tumor / Cell Proliferation - drug effects / Chemotherapy / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Enzyme inhibitors / Epidermal growth factor / Epidermal growth factor receptors / Epidermal growth factors / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Epithelial Cells - pathology / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - genetics / ErbB Receptors - genetics / ErbB Receptors - metabolism / Gefitinib / Gene Expression Regulation, Neoplastic / Humans / Inhibitors / Kinases / Lung cancer / Lung diseases / Medicine and Health Sciences / Mesenchyme / Mutation / Non-small cell lung cancer / Non-small cell lung carcinoma / Patients / Phenols (Class of compounds) / Platinum / Protein Kinase Inhibitors - pharmacology / Protein-tyrosine kinase / Quinazolines - pharmacology / Research and Analysis Methods / Sensitivity / Signal Transduction / Small cell lung cancer / Snail Family Transcription Factors - genetics / Snail Family Transcription Factors - metabolism / Stem cells / Tyrosine / Tyrosine kinase inhibitors