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Updated: May 4, 2026

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Integrin-targeting cyclic peptides suppress TGF-β1-driven EMT and invasion in third-generation EGFR-TKI-resistant

Jay Seo1, Jiyeon Kim1

  • 1Department of Biomedical Laboratory Science, School of Health Science, Dankook University, Cheonan, 31116, Republic of Korea.

Chemico-Biological Interactions
|May 2, 2026
PubMed

Insights

Cilengitide and its derivatives combat drug resistance in non-small cell lung cancer (NSCLC) by inhibiting epithelial-mesenchymal transition (EMT). These compounds, particularly R-8, show promise in 3D models and combination therapy for overcoming resistance to EGFR-TKIs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Third-generation EGFR-TKIs (e.g., naquotinib, osimertinib) face resistance in non-small cell lung cancer (NSCLC) treatment.
  • Epithelial-mesenchymal transition (EMT) is a critical mechanism driving drug resistance and metastasis in NSCLC.
  • Cilengitide, an integrin-targeting peptide, shows potential in suppressing EMT-associated signaling.

Purpose of the Study:

  • To investigate the efficacy of cilengitide and its derivatives in inhibiting TGF-β1-induced EMT, migration, and invasion in EGFR-TKI-resistant NSCLC cells.
  • To evaluate the effectiveness of cilengitide derivatives (R-1, R-7, R-8) in 2D and 3D culture models.
  • To assess the synergistic potential of combination therapy with dovitinib, an FGFR inhibitor.

Main Methods:

  • Establishment of naquotinib- and osimertinib-resistant HCC827 cell lines.
  • Assessment of EMT markers, cell viability, migration, and invasion using qRT-PCR, western blotting, wound-healing, and invasion assays.
  • Utilized 2D and 3D organoid models for evaluating drug efficacy and combination treatments.

Main Results:

  • Resistant NSCLC cells displayed reduced epithelial and increased mesenchymal markers upon TGF-β1 stimulation, correlating with enhanced migration and invasion.
  • Cilengitide and its derivatives significantly inhibited TGF-β1-induced EMT, migration, and invasion, with enhanced efficacy in 3D organoid models.
  • Cilengitide derivative R-8 demonstrated potent suppression of vimentin expression and ERK1/2 phosphorylation; combination with dovitinib showed synergistic effects.

Conclusions:

  • Cilengitide and its derivatives are effective in suppressing EMT, migration, and invasion in EGFR-TKI-resistant NSCLC cells, particularly in 3D models.
  • Cilengitide derivative R-8 shows significant potential for overcoming drug resistance.
  • Combination therapy with dovitinib may offer a synergistic approach to enhance treatment efficacy in resistant NSCLC.
Keywords:
CilengitideInvasionMigrationNSCLCNaquotinibOsimertinib

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