Frontiers in oncology · 2026
The STAT3-ZEB1 axis contributes to CCL2-mediated resistance to osimertinib in lung cancer.
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Chang Tzu-Hua, Tsai Meng-Feng, Wu Shang-Gin, Liu Yi-Nan, Wu Huey-Dong, Tsai Tzu-Hsiu, Jheng Han-Nian, Hsu Chia-Lang, Yeh Pu-Sheng, Shih Jin-Yuan
Аннотация
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.
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.