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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Characteristics of dasatinib- and imatinib-resistant chronic myelogenous leukemia cells

Seiichi Okabe1, Tetsuzo Tauchi, Kazuma Ohyashiki

  • 1First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan. okabe@tokyo-med.ac.jp

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 3, 2008
PubMed
Abstract

Insights

This study reveals that reduced BCR/ABL protein levels contribute to dasatinib resistance in chronic myelogenous leukemia cells. Understanding these resistance mechanisms may improve future therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Dasatinib is a dual src-family kinase/BCR/ABL inhibitor effective against imatinib-resistant chronic myelogenous leukemia (CML).
  • The precise mechanisms underlying resistance to dasatinib, however, remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms responsible for resistance to dasatinib in chronic myelogenous leukemia (CML).
  • To investigate intracellular signaling pathways and protein expression in dasatinib-resistant CML cell lines.

Main Methods:

  • Established imatinib-resistant (IM-R) and dasatinib-resistant (BMS-R) TF-1 BCR/ABL and K562 cell lines.
  • Characterized drug-resistant cells using fluorescence in situ hybridization, western blotting, and analysis of intracellular signaling pathways (MAPK, Akt, Lck).

Main Results:

  • No increase in BCR/ABL gene copy number or mutations were observed in resistant cells.
  • Dasatinib resistance was associated with reduced BCR/ABL protein levels, which were restored by an ubiquitin inhibitor.
  • Activation of Src kinase (Lck), MAPK, and Akt pathways, alongside reduced p21(WAF) and PTEN, was noted in resistant cells.
  • Cessation of dasatinib treatment in resistant cells induced apoptosis, evidenced by caspase 3 and PARP activation.

Conclusions:

  • Reduced BCR/ABL protein expression is a key mechanism of dasatinib resistance in CML.
  • Aberrant intracellular signaling pathways contribute to the development of resistance.
  • These findings offer insights into therapeutic strategies for overcoming dasatinib and imatinib resistance in CML.

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