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CCL2 promotes EGFR-TKIs resistance in non-small cell lung cancer via the AKT-EMT pathway

Yunlian Diao1,2, Shibo Huang3, Fangpeng Liu2

  • 1Jiangxi Provincial Key Laboratory of Prevention and Treatment of Infectious Diseases, Jiangxi Medical Center for Major Public Health Events, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.

Acta Biochimica Et Biophysica Sinica
|July 4, 2024
PubMed

Insights

Chemokine ligand 2 (CCL2) drives acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). Inhibiting CCL2 can overcome this resistance and reduce cancer cell migration by targeting the AKT-epithelial-mesenchymal transition pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge in non-small cell lung cancer (NSCLC) treatment.
  • Chemokine (C-C motif) ligand 2 (CCL2) has emerged as a key factor influencing anti-cancer treatment outcomes.
  • The precise role of CCL2 in the development of EGFR-TKI resistance in NSCLC remains incompletely understood.

Purpose of the Study:

  • To investigate the function and mechanism of CCL2 in acquired resistance to EGFR-TKIs in NSCLC cells.
  • To determine if CCL2 modulation can reverse EGFR-TKI resistance.
  • To elucidate the signaling pathways involved in CCL2-mediated resistance.

Main Methods:

  • Analysis of CCL2 expression in EGFR-TKI-resistant NSCLC cells.
  • Assessment of sensitivity to EGFR-TKIs following CCL2 manipulation (inhibition or knockdown).
  • Evaluation of cell migration and epithelial-mesenchymal transition (EMT) markers.
  • Investigation of the AKT-EMT signaling pathway.

Main Results:

  • CCL2 was found to be aberrantly upregulated in EGFR-TKI-resistant NSCLC cells, correlating with diminished sensitivity to EGFR-TKIs.
  • Suppression of CCL2, using bindarit or siRNA, reversed EGFR-TKI resistance and reduced cell migration and EMT marker expression.
  • CCL2 upregulation promoted cell migration and EMT, which was dependent on the AKT-EMT signaling pathway.

Conclusions:

  • CCL2 plays a significant role in promoting acquired resistance to EGFR-TKIs in NSCLC.
  • CCL2 contributes to increased cell migration and EMT via the AKT signaling pathway.
  • Targeting CCL2 presents a potential therapeutic strategy to overcome EGFR-TKI resistance in NSCLC.
Keywords:
CCL2EGFR-TKIs resistanceepithelial-mesenchymal transitionnon-small cell lung cancer

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