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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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Pharmacological interplay between breast cancer resistance protein and gefitinib in epidermal growth factor receptor

Kazuhiro Katayama1, Kazuhiko Shibata, Junko Mitsuhashi

  • 1Division of Chemotherapy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.

Anticancer Research
|May 6, 2009
PubMed
Abstract

Insights

Breast cancer resistance protein (BCRP) transports gefitinib, reducing its effectiveness in inhibiting epidermal growth factor receptor (EGFR) signaling. This BCRP-mediated resistance is primarily observed in gefitinib-sensitive cells.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cancer Research

Background:

  • Gefitinib is known to reverse breast cancer resistance protein (BCRP)-mediated drug resistance.
  • The role of BCRP in gefitinib's inhibition of epidermal growth factor receptor (EGFR) signaling requires further investigation.

Purpose of the Study:

  • To evaluate the impact of BCRP on gefitinib's inhibition of EGFR signaling.
  • To determine if BCRP influences gefitinib sensitivity and resistance.

Main Methods:

  • Cell sensitivity to gefitinib was assessed using growth inhibition assays.
  • Intracellular gefitinib concentrations were quantified via High-Performance Liquid Chromatography (HPLC).
  • EGFR signaling pathway components were analyzed using Western blotting.

Main Results:

  • BCRP decreased intracellular gefitinib levels and weakened its inhibitory effects on EGF-dependent EGFR signaling, including MAPK and Akt pathways, in gefitinib-sensitive PC-9 cells.
  • In gefitinib-insensitive KB-3-1 and HCT-116 cells, gefitinib did not inhibit MAPK and Akt signaling, and BCRP-mediated resistance was not observed.
  • BCRP was identified as a transporter of gefitinib, suppressing its inhibitory action on EGFR phosphorylation.

Conclusions:

  • BCRP actively transports gefitinib and diminishes its inhibitory effects on EGFR phosphorylation.
  • The influence of BCRP on gefitinib's activity within EGFR signaling and its contribution to gefitinib resistance are significant primarily in gefitinib-sensitive cell lines.

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