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Folic Acid-Modified Milk Exosomes Delivering c-Kit siRNA Overcome EGFR-TKIs Resistance in Lung Cancer by Suppressing

Zihan Xu1,2,3, Li Wang1,2, Li Tu1,2

  • 1Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China, 610041.

International Journal of Biological Sciences
|January 2, 2025
PubMed

Insights

Novel folic acid-modified milk exosomes carrying c-kit siRNA overcome resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in lung cancer. This approach targets the c-kit/mTOR pathway, reducing cancer stemness and improving treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Nanomedicine

Background:

  • Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are vital for lung cancer treatment.
  • Acquired resistance to EGFR-TKIs significantly limits patient prognosis.
  • Novel strategies are essential to overcome EGFR-TKI resistance.

Purpose of the Study:

  • To investigate folic acid-modified milk exosomes loaded with c-kit siRNA (FA-mExo-siRNA-c-kit) as a therapeutic strategy against EGFR-TKI resistance in lung cancer.
  • To elucidate the role of c-kit in promoting stemness and resistance to gefitinib.
  • To explore the therapeutic potential of FA-mExo-siRNA-c-kit in preclinical models of EGFR-TKI-resistant lung cancer.

Main Methods:

  • Characterization of gefitinib-resistant lung cancer cells for stemness markers and c-kit expression.
  • In vitro evaluation of FA-mExo-siRNA-c-kit treatment on c-kit expression, stemness, and gefitinib sensitivity.
  • In vivo assessment of FA-mExo-siRNA-c-kit and gefitinib combination therapy in xenograft and liver metastasis models.
  • Mechanistic studies on the c-kit/AKT/mTOR/4EBP1/eIF4E signaling pathway.

Main Results:

  • Gefitinib-resistant lung cancer cells displayed stemness and epithelial-to-mesenchymal transition phenotypes regulated by c-kit.
  • FA-mExo-siRNA-c-kit effectively suppressed c-kit expression and stemness traits in vitro, restoring gefitinib sensitivity.
  • Combined sequential administration of FA-mExo-siRNA-c-kit and gefitinib reduced tumor growth and prolonged survival in vivo.
  • c-kit was identified as a key regulator of the AKT/mTOR/4EBP1/eIF4E pathway, driving stemness and gefitinib resistance.

Conclusions:

  • c-kit plays a critical role in promoting stemness and EGFR-TKI resistance in lung cancer via the mTOR pathway.
  • FA-mExo-siRNA-c-kit represents a promising therapeutic strategy for overcoming EGFR-TKI resistance, particularly in cases with liver metastasis.
  • This novel nanomedicine approach holds potential for improving outcomes in EGFR-TKI-resistant lung cancer patients.
Keywords:
EGFR-TKIs resistancec-kitmilk exosomesnon-small cell lung cancerstemness

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