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Updated: Feb 1, 2026

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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[MET/ERK and MET/JNK Pathway Activation Is Involved in BCR-ABL Inhibitor-resistance in Chronic Myeloid Leukemia]

Masanobu Tsubaki1

  • 1Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University.

Yakugaku Zasshi : Journal of the Pharmaceutical Society of Japan
|December 4, 2018
PubMed

Insights

Resistance to imatinib, a tyrosine kinase inhibitor (TKI), in chronic myeloid leukemia (CML) can occur without BCR-ABL1 mutations. MET receptor tyrosine kinase activation drives this resistance, suggesting MET inhibitors as a potential therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Imatinib is a crucial tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML) treatment.
  • Resistance to imatinib, often due to BCR-ABL1 mutations, limits treatment efficacy.
  • BCR-ABL1-independent imatinib resistance mechanisms require further investigation.

Purpose of the Study:

  • To elucidate the mechanisms underlying BCR-ABL1-independent imatinib resistance in CML.
  • To identify novel therapeutic targets for overcoming imatinib resistance in CML.

Main Methods:

  • Array-based comparative genomic hybridization (aCGH) was employed to identify resistance-related genes.
  • In vitro studies utilized K562/IR cells treated with imatinib and a MET inhibitor.
  • In vivo tumor growth suppression was assessed in a relevant model.

Main Results:

  • The receptor tyrosine kinase MET was identified as a key player in imatinib resistance.
  • MET inhibition resensitized resistant cells (K562/IR) to imatinib.
  • Combined imatinib and MET inhibitor treatment suppressed tumor growth in vivo.
  • This combination therapy inhibited MET/ERK and MET/JNK signaling pathways, but not AKT.

Conclusions:

  • MET activation represents a significant mechanism of BCR-ABL1-independent imatinib resistance in CML.
  • Targeting MET, in combination with imatinib, offers a promising therapeutic strategy for resistant CML.
  • MET and associated signaling pathways (ERK, JNK) are potential targets for novel CML therapies.
Keywords:
METchronic myeloid leukemiaimatinib resistance

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