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The STAT3-ZEB1 axis contributes to CCL2-mediated resistance to osimertinib in lung cancer
Tzu-Hua Chang1, Meng-Feng Tsai2, Shang-Gin Wu1,3
1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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.
Insights
Discover a new pathway driving osimertinib resistance in non-small cell lung cancer (NSCLC). Targeting CCL2-STAT3-ZEB1 signaling, not AKT, can overcome resistance, offering new hope for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), treats NSCLC with specific mutations.
- Acquired resistance to osimertinib is a significant clinical challenge.
- CCL2's role in EGFR-TKI resistance via AKT activation is known, but downstream mechanisms remain unclear.
Purpose of the Study:
- To elucidate the precise downstream signaling pathways mediating CCL2-induced osimertinib resistance in NSCLC.
- To identify novel therapeutic targets for overcoming acquired resistance to osimertinib.
Main Methods:
- Analysis of malignant pleural effusion samples from NSCLC patients with acquired resistance.
- Functional assays in lung cancer cell lines with CCL2 manipulation (overexpression/knockdown).
- In vivo xenograft models to validate findings and assess therapeutic strategies.
Main Results:
- CCL2 was significantly upregulated in resistant NSCLC samples.
- CCL2 overexpression conferred osimertinib resistance; CCL2 knockdown restored sensitivity.
- CCL2 induced resistance via STAT3 and ERK1/2-dependent ZEB1 upregulation, independent of AKT.
- Combined STAT3 inhibition and osimertinib reversed resistance in preclinical models.
Conclusions:
- A novel CCL2-STAT3-ZEB1 signaling axis drives acquired osimertinib resistance in NSCLC.
- Targeting STAT3 concurrently with EGFR may offer a promising strategy to improve osimertinib efficacy in NSCLC patients.
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