Rab25 promotes erlotinib resistance by activating the β1 integrin/AKT/β‐catenin pathway in NSCLC. (7th March 2019)

• Record Type: Journal Article
• Authors: Wang, Jianmin; Zhou, Pu; Wang, Xudong; Yu, Yongxin; Zhu, Guangkuo; Zheng, Linpeng; Xu, Zihan; Li, Feng; You, Qiai; Yang, Qiao; Zhuo, Wenlei; Sun, Jianguo; Chen, Zhengtang
• Is Part Of: Cell proliferation. Volume 52:Number 3(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-03-07
• Subjects: EGFR‐TKI resistance -- NSCLC -- Rab25 -- β1 integrin -- β‐catenin; Cell proliferation -- Periodicals; 571.84
• DOI: 10.1111/cpr.12592
• Languages: English
• ISSNs: 0960-7722

Abstract

Abstract: 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.