The CCL2-CCR2 axis contributes to acquired osimertinib resistance in lung cancer by upregulating Zeb1 expression

Abstract Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), effectively treats non-small-cell lung cancer patients with EGFR activation mutations or those with acquired T790M resistance mutation following EGFR-TKIs therapy. However, the development of drug resistance remains a significant clinical challenge. Therefore, we aimed to investigate novel cytokine signaling pathways contributing to osimertinib resistance in lung cancer. Our findings revealed that the CCL2-CCR2 signaling pathway is pivotal in osimertinib resistance development. We observed elevated CCL2 expression in EGFR TKIs-resistant lung cancer cells compared to treatment-naive EGFR mutant cells. Furthermore, ectopic expression of CCL2 in osimertinib-sensitive lung cancer cells conferred resistance to osimertinib in vitro and in vivo. CCL2 knockdown improved osimertinib-induced apoptosis in lung cancer cells. Osimertinib-resistant cells exhibited epithelial-mesenchymal transition phenotypes. We demonstrated that CCL2 primarily confers osimertinib resistance through CCR2, STAT3, and ERK, upregulating Zeb1 expression. Finally, combining a STAT3 inhibitor with osimertinib overcoming resistance in vivo. In conclusion, CCL2 significantly contributes to acquired osimertinib resistance in lung cancer. Targeting the CCL2-CCR2-STAT3/ERK-Zeb1 signaling pathway holds therapeutic potential for overcoming osimertinib resistance and improving treatment outcomes.