Journal Article

Rab25 promotes erlotinib resistance by activating the β1 integrin/AKT/β‐catenin pathway in NSCLC

Zhuo, Wenlei, Yang, Qiao, Li, Feng, Zhu, Guangkuo, Chen, Zhengtang, Zhou, Pu, Sun, Jianguo, Yu, Yongxin, Zheng, Linpeng, Xu, Zihan, You, Qiai, Wang, Jianmin, Wang, Xudong

2019

Overview

Objectives Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) has significant therapeutic efficacy in non‐small‐cell lung cancer (NSCLC) patients. However, acquired resistance is inevitable and limits the long‐term efficacy of EGFR‐TKI. Our study aimed to investigate the role of ras‐associated binding protein 25 (Rab25) in mediating EGFR‐TKI resistance in NSCLC. Materials and Methods Rab25 expression in NSCLC patients was measured by immunohistochemical staining. Western blotting was used to analyse the expression of molecules in the Rab25, EGFR and Wnt signalling pathways. Lentiviral vectors were constructed to knock in and knock out Rab25. The biological function of Rab25 was demonstrated by cell‐counting kit‐8 and flow cytometry. The interaction between Rab25 and β1 integrin was confirmed by co‐immunoprecipitation. Results Rab25 overexpression induced erlotinib resistance, whereas Rab25 knockdown reversed this refractoriness in vitro and in vivo. Moreover, Rab25 interacts with β1 integrin and promotes its trafficking to the cytoplasmic membrane. The membrane‐β1 integrin induced protein kinase B (AKT) phosphorylation and subsequently activated the Wnt/β‐catenin signalling pathway, promoting cell proliferation. Furthermore, high Rab25 expression was associated with poor response to EGFR‐TKI treatment in NSCLC patients. Conclusions Rab25 mediates erlotinib resistance by activating the β1 integrin/AKT/β‐catenin signalling pathway. Rab25 may be a predictive biomarker and has potential therapeutic value in NSCLC patients with acquired resistance to EGFR‐TKI.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Adenocarcinoma of Lung - drug therapy / Adenocarcinoma of Lung - metabolism / AKT protein / Animals / Antineoplastic Agents - pharmacology / beta Catenin - metabolism / Biomarkers / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - metabolism / Catenin / Cell proliferation / Drug Resistance, Neoplasm / EGFR‐TKI resistance / Enzyme inhibitors / Epidermal growth factor / Epidermal growth factor receptors / Erlotinib Hydrochloride - pharmacology / Flow cytometry / Gene Knockdown Techniques / Growth factors / Humans / Immunoprecipitation / Integrin beta1 - metabolism / Kinases / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - metabolism / Male / Membrane proteins / Membrane trafficking / Mice / Mice, Nude / Non-small cell lung carcinoma / NSCLC / Original / Phosphorylation / Protein Kinase Inhibitors - pharmacology / Protein-tyrosine kinase receptors / Proteins / Proto-Oncogene Proteins c-akt - metabolism / rab GTP-Binding Proteins - antagonists & inhibitors / rab GTP-Binding Proteins - genetics / rab GTP-Binding Proteins - metabolism / Rab25 / Signal transduction / Signal Transduction - drug effects / Signaling / Thermal resistance / Tyrosine / Western blotting / Wnt protein / Xenograft Model Antitumor Assays / β1 integrin / β‐catenin