The STAT3-ZEB1 axis contributes to CCL2-mediated resistance to osimertinib in lung cancer.
Journal
Frontiers in oncology
Journal Volume
16
Start Page
Article number 1699471
ISSN
2234-943X
Date Issued
2026
Author(s)
Chang, Tzu-Hua
Tsai, Meng-Feng
Liu, Yi-Nan
Jheng, Han-Nian
Yeh, Pu-Sheng
Abstract
Objective: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is effective in NSCLC patients with EGFR-activating or T790M mutations, but acquired resistance remains a major challenge. Although CCL2 has been implicated in EGFR-TKI resistance via AKT activation, the precise downstream mechanisms are not fully understood. Methods: We analyzed malignant pleural effusion samples from patients with resistant NSCLC and conducted functional assays in lung cancer cell lines with ectopic CCL2 expression or knockdown, combined with in vivo xenograft models. Key downstream signaling pathways were interrogated. Results: CCL2 was significantly upregulated in resistant patient samples. Overexpression of CCL2 induced osimertinib resistance, whereas silencing restored drug sensitivity. Mechanistically, CCL2 promoted resistance through STAT3- and ERK1/2-dependent upregulation of ZEB1, rather than via the AKT pathway. Notably, combined STAT3 inhibition and osimertinib effectively reversed resistance in xenografts. Conclusion: These findings uncover a novel CCL2–STAT3–ZEB1 signaling axis that drives acquired osimertinib resistance in NSCLC. Dual targeting of STAT3 and EGFR may represent a promising therapeutic approach to improve clinical outcomes.
Subjects
CCL2
STAT3
ZEB1
epithelial to mesenchymal transition
osimertinib resistance
Type
journal article