Non‑enzymatic function of QSOX2 directly regulates the JUNB‑ITGB4 axis and enhances resistance to osimertinib in EGFR‑mutation lung adenocarcinoma
QSOX2 promotes osimertinib resistance in EGFR‑mutant lung adenocarcinoma by non‑enzymatically regulating the JUNB‑ITGB4 signaling axis.
Third‑generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‑TKIs) represent a significant advancement in the targeted therapy of lung adenocarcinoma (LUAD), markedly prolonging patient overall survival. However, resistance remains a major barrier to sustained clinical benefit. Beyond the classical EGFR resistance pathways, EGFR‑independent bypass mechanisms have emerged as a critical research focus. Quiescent sulfhydryl oxidase 2 (QSOX2), linked to poor outcomes in various cancers, remains poorly studied in LUAD, with its role in tumor progression mechanisms largely unknown. In this study, we demonstrated that the specific high expression of QSOX2 in LUAD induced osimertinib resistance (OR). Mechanistically, QSOX2 directly binds to and stabilizes the transcription factor JUNB via a non‑enzymatic interaction, promoting JUNB phosphorylation and nuclear translocation through AKT pathway activation. This results in the transcriptional activation of ITGB4, which in turn initiates FAK/AKT signaling to establish a positive feedback loop that ultimately drives osimertinib bypass resistance. In conclusion, this study innovatively identified the non‑enzymatic function of QSOX2 in regulating OR in EGFR‑mutant LUAD through the JUNB‑ITGB4‑FAK/AKT pathway. The QSOX2/JUNB‑ITGB4 signaling axis represents a potential therapeutic target for overcoming OR and offers a novel strategy to improve outcomes in LUAD patients.
Identifying QSOX2’s non‑enzymatic role in triggering osimertinib resistance uncovers a novel therapeutic target and provides a basis for strategies to restore drug sensitivity in EGFR‑mutant lung adenocarcinoma.
Evidence level: Állatkísérletes. Állatmodellben vizsgálták.
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