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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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[Relationship between EGFR Promoter Region Methylation and Secondary Resistance Which may be Induced by Gefitinib]

Qilong Wang1, Min Li1, Chengping Hu1

  • 1Department of Respiratory Medicine, Xiangya Hospital of Central South University, Changsha 410008, China.

Zhongguo Fei AI Za Zhi = Chinese Journal of Lung Cancer
|May 5, 2015
PubMed
Abstract

Insights

This study demonstrates that increasing gefitinib concentration induces resistance in lung adenocarcinoma cells, linked to epidermal growth factor receptor (EGFR) promoter methylation. This finding suggests EGFR methylation as a potential therapeutic target for overcoming gefitinib resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Secondary resistance to gefitinib is a significant challenge in treating lung adenocarcinoma.
  • Understanding the mechanisms of gefitinib resistance is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate if gefitinib can induce secondary resistance in lung adenocarcinoma cells.
  • To determine the correlation between epidermal growth factor receptor (EGFR) promoter methylation and gefitinib resistance.
  • To identify potential therapeutic targets for overcoming gefitinib resistance.

Main Methods:

  • Cultured lung adenocarcinoma PC9 cells and induced gefitinib resistance by increasing drug concentration.
  • Assessed gefitinib resistance using MTT assays.
  • Analyzed EGFR promoter methylation and mRNA expression via Bisulfite sequencing polymerase chain reaction (BSP) and Reverse transcription-polymerase chain reaction (RT-PCR).
  • Treated resistant PC9/GR cells with 5-Aza-dc to evaluate its effect on gefitinib resistance.

Main Results:

  • Gefitinib treatment significantly increased the IC50 (resistance) in PC9 cells from 0.01 to 3.95 μmol/L.
  • PC9/GR cells exhibited increased EGFR promoter methylation (74%) and elevated EGFR mRNA expression compared to PC9 cells.
  • Treatment with 5-Aza-dc reduced the gefitinib IC50 in PC9/GR cells from 3.87 to 2.55 μmol/L.

Conclusions:

  • Gefitinib-induced resistance can be established in PC9 lung adenocarcinoma cells, creating a resistant PC9/GR cell line.
  • EGFR gene promoter methylation is implicated as a key mechanism contributing to secondary gefitinib resistance.
  • Targeting EGFR methylation presents a potential strategy to overcome gefitinib resistance in lung adenocarcinoma.

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