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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are effective against non-small-cell lung cancer (NSCLC).
• Acquired resistance to EGFR-TKI is a major clinical challenge, limiting long-term patient outcomes.
• Understanding the mechanisms of acquired resistance is crucial for developing improved therapeutic strategies.

Purpose of the Study:

• To investigate the role of ras-associated binding protein 25 (Rab25) in mediating acquired resistance to EGFR-TKI in NSCLC.
• To elucidate the molecular pathways through which Rab25 contributes to EGFR-TKI resistance.

Main Methods:

• Immunohistochemical staining to assess Rab25 expression in NSCLC patient samples.
• Western blotting to analyze signaling pathway components (Rab25, EGFR, Wnt).
• Lentiviral vectors for Rab25 knockdown and overexpression studies.
• Cell proliferation assays (cell-counting kit-8) and flow cytometry to evaluate cellular functions.
• Co-immunoprecipitation to confirm the interaction between Rab25 and β1 integrin.

Main Results:

• Rab25 overexpression conferred erlotinib resistance in vitro and in vivo, while Rab25 knockdown reversed resistance.
• Rab25 interacts with β1 integrin, promoting its translocation to the cell membrane.
• Membrane-localized β1 integrin activated AKT phosphorylation, subsequently activating the Wnt/β-catenin pathway and promoting cell proliferation.
• High Rab25 expression correlated with a poorer response to EGFR-TKI treatment in NSCLC patients.

Conclusions:

• Rab25 mediates erlotinib resistance in NSCLC by activating the β1 integrin/AKT/β-catenin signaling cascade.
• Rab25 shows potential as a predictive biomarker for EGFR-TKI response in NSCLC.
• Targeting Rab25 may represent a promising therapeutic strategy for overcoming acquired resistance to EGFR-TKI in NSCLC.