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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
09:38

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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Elevated BCRP/ABCG2 expression confers acquired resistance to gefitinib in wild-type EGFR-expressing cells

Yun-Ju Chen1, Wei-Chien Huang, Ya-Ling Wei

  • 1Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.

Plos One
|July 7, 2011
PubMed
Abstract

Insights

Breast cancer resistance protein (BCRP/ABCG2) elevates in wild-type EGFR non-small cell lung cancer, causing resistance to gefitinib. Targeting BCRP/ABCG2 may improve treatment efficacy in these patients.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • EGFR mutations drive sensitivity to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC).
  • Some wild-type EGFR (wtEGFR) NSCLC patients respond to EGFR TKIs, indicating unknown resistance mechanisms.
  • Most wtEGFR NSCLC cells are insensitive to EGFR TKIs, necessitating further investigation.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to gefitinib in wtEGFR NSCLC.
  • To identify potential biomarkers for predicting gefitinib response in wtEGFR NSCLC.
  • To explore therapeutic strategies to overcome gefitinib resistance in wtEGFR NSCLC.

Main Methods:

  • Assessed the role of breast cancer resistance protein (BCRP/ABCG2) in gefitinib resistance in wtEGFR NSCLC cells.
  • Correlated BCRP/ABCG2 expression with gefitinib response in NSCLC cell lines and patient cohorts.
  • Evaluated the efficacy of co-treatment with BCRP/ABCG2 inhibitors and gefitinib.

Main Results:

  • Elevated BCRP/ABCG2 expression was associated with acquired gefitinib resistance in wtEGFR NSCLC cells.
  • BCRP/ABCG2 facilitates gefitinib efflux from cancer cells.
  • BCRP/ABCG2 expression correlated with poor gefitinib response in both cell lines and NSCLC patients with wtEGFR.
  • Co-administration of BCRP/ABCG2 inhibitors enhanced gefitinib's anti-tumor activity.

Conclusions:

  • BCRP/ABCG2 expression may serve as a predictive biomarker for gefitinib treatment efficacy in wtEGFR NSCLC.
  • Targeting BCRP/ABCG2 presents a potential strategy to broaden the clinical application of gefitinib in wtEGFR NSCLC patients.

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