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Updated: Jun 25, 2025

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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ABCG2 Mediates Resistance to the Dual EGFR and PI3K Inhibitor MTX-211 in Cancer Cells

Chung-Pu Wu1,2,3,4, Cheng-Yu Hung3, Megumi Murakami5

  • 1Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.

International Journal of Molecular Sciences
|May 25, 2024
PubMed

Insights

Multidrug resistance protein ABCG2 causes resistance to the cancer drug MTX-211 by pumping it out of cells. This reduces MTX-211

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • MTX-211 is a novel dual inhibitor targeting EGFR and PI3K pathways.
  • Acquired resistance mechanisms to MTX-211 in human cancers are not well understood.
  • EGFR and PI3K pathways are crucial in various cancers, including colorectal tumors with KRAS mutations.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to MTX-211.
  • To determine the role of ATP-binding cassette (ABC) drug transporters in MTX-211 resistance.
  • To elucidate the interaction between MTX-211 and ABCG2.

Main Methods:

  • Investigated the effect of ABCG2 overexpression on MTX-211 effectiveness in human cancer cells.
  • Measured intracellular accumulation of MTX-211 in cancer cells with varying ABCG2 levels.
  • Assessed MTX-211-stimulated ATPase activity of ABCG2.
  • Performed computational molecular docking analysis.

Main Results:

  • Overexpression of ABCG2 significantly diminished MTX-211 effectiveness and cytotoxicity.
  • ABCG2 actively effluxes MTX-211, reducing its intracellular concentration.
  • MTX-211 was identified as a substrate for ABCG2, confirmed by ATPase activity and docking studies.
  • Cancer cells overexpressing ABCG2 showed attenuated suppression of EGFR and PI3K pathways by MTX-211.

Conclusions:

  • ABCG2 is involved in the emergence of acquired resistance to MTX-211.
  • MTX-211 acts as a substrate for the ABCG2 drug transporter.
  • Findings suggest potential clinical strategies to overcome MTX-211 resistance by targeting ABCG2.
Keywords:
ABCG2EGFRMTX-211PI3Kmultidrug resistance

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