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Gefitinib reverses breast cancer resistance protein-mediated drug resistance

Kae Yanase1, Satomi Tsukahara, Sakiyo Asada

  • 1Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan.

Molecular Cancer Therapeutics
|September 16, 2004
PubMed

Insights

Gefitinib, an EGFR inhibitor, interacts with Breast Cancer Resistance Protein (BCRP), reversing its drug resistance. This suggests BCRP influences gefitinib sensitivity and offers a strategy to overcome BCRP-mediated resistance in cancer therapy.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Oncology

Background:

  • Breast cancer resistance protein (BCRP) is an efflux transporter contributing to multidrug resistance in cancer.
  • BCRP actively transports various anticancer agents, limiting their efficacy.
  • Gefitinib is a targeted therapy for specific cancers, but its interaction with BCRP was unclear.

Purpose of the Study:

  • To investigate the interaction between gefitinib and BCRP.
  • To determine if BCRP influences gefitinib sensitivity in cancer cells.
  • To evaluate gefitinib's potential to overcome BCRP-mediated drug resistance.

Main Methods:

  • Cellular assays using BCRP-transduced cancer cell lines (A431/BCRP, K562/BCRP, P388/BCRP) and parental cells.
  • Assessment of gefitinib's effect on drug resistance to SN-38 and topotecan.
  • In vivo studies using BCRP-transduced tumor xenografts in mice.

Main Results:

  • BCRP-transduced cells acquired resistance to gefitinib, indicating BCRP's role in gefitinib sensitivity.
  • Gefitinib reversed resistance to SN-38 and increased topotecan accumulation in BCRP-expressing cells.
  • Gefitinib inhibited BCRP's pump function and demonstrated synergistic effects with irinotecan in vivo.

Conclusions:

  • Gefitinib interacts with BCRP, suggesting BCRP expression is a determinant of gefitinib sensitivity.
  • Gefitinib effectively inhibits BCRP transporter function, overcoming BCRP-mediated drug resistance.
  • Combination therapy with gefitinib shows promise for enhancing cancer treatment outcomes in BCRP-expressing tumors.

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