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

## TL;DR

This study identifies a new pathway involving STAT3 and ZEB1 that causes resistance to osimertinib in lung cancer, suggesting a potential treatment strategy.

## Contribution

The study reveals a novel CCL2–STAT3–ZEB1 axis as a mechanism of osimertinib resistance in NSCLC.

## Key findings

- CCL2 overexpression induces osimertinib resistance in lung cancer cells.
- CCL2 promotes resistance via STAT3- and ERK1/2-dependent upregulation of ZEB1.
- Combining STAT3 inhibition with osimertinib reverses resistance in xenograft models.

## Abstract

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.

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.

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.

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.