Epithelial-mesenchymal transition is associated with osteopontin-induced EGFR‑TKI resistance in EGFR mutant non-small cell lung cancer

Junjie Chen; Lin Shi; Yao Qian; Yi Jin; Nian Dong; Chengshui Chen; Beibei Wang

doi:10.21037/jtd-23-818

Epithelial-mesenchymal transition is associated with osteopontin-induced EGFR‑TKI resistance in EGFR mutant non-small cell lung cancer

J Thorac Dis. 2023 Jun 30;15(6):3359-3371. doi: 10.21037/jtd-23-818. Epub 2023 Jun 26.

Authors

Junjie Chen^#¹, Lin Shi^#², Yao Qian¹, Yi Jin³, Nian Dong¹, Chengshui Chen¹, Beibei Wang¹

Affiliations

¹ Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
² Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Pathology Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

^# Contributed equally.

Abstract

Background: Resistance restricts the long-term therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC) with positive EGFR mutations. The present study sought to identify the potential protein osteopontin (OPN) involved in EGFR-TKI resistance and examine its therapeutic mechanism in NSCLC.

Methods: The expression of OPN in NSCLC tissues was evaluated by immunohistochemistry (IHC). Western blot (WB), quantitative real‑time polymerase chain reaction (qRT-PCR), and immunofluorescence staining were used to analyze OPN and epithelial-mesenchymal transition (EMT)-related protein expression in the PC9 and PC9 gefitinib resistance (PC9GR) cells. Enzyme-linked immunosorbent assays (ELISAs) were used to detect the secreted OPN. Cell Counting Kit-8 (CCK-8) assays and flow cytometry were used to examine the effect of OPN on the gefitinib-induced growth and death of PC9 or PC9GR cells.

Results: OPN was upregulated in the human NSCLC tissues and cells resistant to EGFR-TKIs. The overexpression of OPN inhibited EGFR-TKI-induced apoptosis and was associated with the formation of EMT. By activating the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)-EMT pathway, OPN contributed to the development of EGFR-TKI resistance. Reducing OPN expression and inhibiting PI3K/AKT signaling improved EGFR-TKI sensitivity significantly more than the use of either agent alone.

Conclusions: This study showed that OPN increased EGFR-TKI resistance in NSCLC through the OPN-PI3K/AKT-EMT pathway. Our findings may provide a possible therapeutic target for overcoming EGFR-TKI resistance in this pathway.

Keywords: Osteopontin (OPN); epidermal growth factor receptor-tyrosine kinase inhibitor resistance (EGFR‑TKI resistance); epithelial-mesenchymal transition (EMT); non-small cell lung cancer (NSCLC); phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT).