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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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Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib

Kohji Noguchi1, Haruka Kawahara, Airi Kaji

  • 1Division of Chemotherapy, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo, Japan.

Cancer Science
|June 5, 2009
PubMed

Insights

Erlotinib, an EGFR-TKI, reverses BCRP-mediated drug resistance but has mixed effects on P-glycoprotein-mediated resistance, depending on the drug. This highlights substrate-dependent interactions for combination chemotherapy.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Oncology

Background:

  • Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can affect ATP-binding cassette transporters.
  • Previous work showed gefitinib antagonizes breast cancer resistance protein (BCRP).
  • The effects of erlotinib on P-glycoprotein (P-gp) and BCRP require further investigation.

Purpose of the Study:

  • To analyze the effects of erlotinib on P-glycoprotein and BCRP.
  • To determine if erlotinib can overcome drug resistance mediated by these transporters.
  • To elucidate the mechanism and substrate-dependency of erlotinib's interactions with P-gp and BCRP.

Main Methods:

  • Assessing erlotinib's ability to reverse resistance to various chemotherapy drugs in cell lines expressing P-gp or BCRP.
  • Flow cytometry to analyze intracellular drug accumulation.
  • Intravesicular transport assays to measure transporter activity.
  • Lineweaver-Burk plots to determine inhibition kinetics.

Main Results:

  • Erlotinib reversed BCRP-mediated resistance to SN-38 and mitoxantrone.
  • Erlotinib suppressed P-gp-mediated resistance to vincristine and paclitaxel but enhanced resistance to mitoxantrone and doxorubicin.
  • Erlotinib restored mitoxantrone accumulation in BCRP-expressing cells but not P-gp-expressing cells.
  • Erlotinib inhibited P-gp-mediated vincristine transport and BCRP-mediated estrone 3-sulfate transport with different inhibition kinetics.

Conclusions:

  • Erlotinib's impact on P-glycoprotein-mediated drug resistance is substrate-dependent.
  • Erlotinib's interactions with P-gp and BCRP vary based on the specific transporter and drug substrate.
  • Findings are crucial for understanding erlotinib's role in combination chemotherapy and predicting drug interactions.

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