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ORIGINAL RESEARCH article

Front. Oncol.

Sec. Thoracic Oncology

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

Provisionally accepted
Tzu-Hua ChangTzu-Hua Chang1Meng-Feng TsaiMeng-Feng Tsai2Shang-Gin WuShang-Gin Wu3Yi-Nan LiuYi-Nan Liu1Huey-Dong WuHuey-Dong Wu4Tzu-Hsiu TsaiTzu-Hsiu Tsai3Han-Nian JhengHan-Nian Jheng1Chia-Lang HsuChia-Lang Hsu5Pu Sheng YehPu Sheng Yeh6Jin-Yuan ShihJin-Yuan Shih1*Pu Sheng YehPu Sheng Yeh6
  • 1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
  • 2Department of Biomedical Sciences, Da-Yeh University, Changhua, Taiwan
  • 3Department of Internal Medicine, National Taiwan University Cancer Center, Taipei, Taiwan
  • 4Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan
  • 5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
  • 6Department of Critical Care Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan

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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.

Keywords: CCL2, Epithelial to Mesenchymal transition, Osimertinib resistance, stat3, Zeb1

Received: 05 Sep 2025; Accepted: 29 Jan 2026.

Copyright: © 2026 Chang, Tsai, Wu, Liu, Wu, Tsai, Jheng, Hsu, Yeh, Shih and Yeh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Jin-Yuan Shih

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material