Reprogramming Tumor-Associated Macrophages To Reverse EGFRT790M Resistance by Dual-Targeting Codelivery of

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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

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Huige Peng1,2, Binfan Chen1,2, Wei Huang1

  • 1Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.

Nano Letters
|November 22, 2017
PubMed

Insights

This study introduces a novel drug delivery system to overcome resistance in non-small cell lung cancer (NSCLC) with EGFR T790M mutations. The strategy reprograms tumor-associated macrophages (TAMs) to resensitize cancer cells to gefitinib.

Area of Science:

  • Oncology
  • Nanotechnology
  • Pharmacology

Background:

  • Gefitinib is a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC).
  • Drug resistance, particularly due to the EGFR T790M mutation, limits the efficacy of targeted therapies like gefitinib and osimertinib.
  • Tumor-associated macrophages (TAMs) play a role in promoting drug resistance in NSCLC.

Purpose of the Study:

  • To develop a dual-targeting codelivery system to overcome EGFR T790M-associated drug resistance in NSCLC.
  • To reprogram TAMs from a pro-tumor M2 phenotype to an anti-tumor M1 phenotype.
  • To resensitize EGFR T790M-positive NSCLC cells to gefitinib.

Main Methods:

  • A trastuzumab-modified, mannosylated liposomal system was designed for codelivery of gefitinib and vorinostat.
  • The system targeted TAMs overexpressing mannose receptors and HER-2 positive NSCLC cells.
  • The strategy involved repolarizing TAMs, elevating reactive oxygen species (ROS) in cancer cells, and modulating the ROS/NOX3/MsrA axis.

Main Results:

  • The liposomal system successfully repolarized M2 TAMs to M1.
  • Elevated ROS levels suppressed MsrA, facilitating EGFR T790M degradation via oxidation.
  • This process resensitized EGFR T790M-positive NSCLC cells to gefitinib, overcoming drug resistance.

Conclusions:

  • A dual-targeting codelivery system combined with TAM reprogramming offers a potential strategy to overcome EGFR T790M-mediated resistance to tyrosine kinase inhibitors.
  • This approach provides a promising method for enhancing the efficacy of NSCLC treatment in resistant cases.
Keywords:
EGFRT790MTumor-associated macrophagesdrug resistancegefitinibnonsmall cell lung cancervorinostat

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