The STAT3–ZEB1 axis contributes to CCL2-mediated resistance to osimertinib in lung cancer

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: 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.