Tyrosine kinase inhibitor resistance in chronic myeloid leukemia cell lines: Investigating resistance pathways

Carine Tang, Lisa Schafranek, Dale B. Watkins, Wendy T. Parker, Sarah Moore, Jodi A. Prime, Deborah L. White, Timothy P. Hughes

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

There are three currently identified secondary resistance mechanisms observed in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). These are BCRABL kinase domain (KD) mutations, increased BCRABL expression, and overexpression of drug-efflux proteins (ABCB1 and ABCG2). To investigate the interplay between these three modes of resistance, three CML blast crisis cell lines (K562, its ABCB1-overexpressing variant K562 Dox, and KU812) were cultured in gradually increasing concentrations of imatinib to 2 μM, or dasatinib to 200 nM. Eight imatinib-and two dasatinib-resistant cell lines were established. Two imatinib-resistant K562 lines both had increased BCRABL expression as the apparent mode of resistance. However, when a dasatinib-resistant K562 culture was generated we observed gradually increasing BCRABL expression which peaked prior to identification of the T315I mutation. BCRABL overexpression followed by mutation development was observed in a further 4/10 cell lines, each with different KD mutations. In contrast, three imatinib-resistant K562 Dox lines exhibited only a further increase in ABCB1 expression. All TKI-resistant cell lines generated had increased IC 50 (dose of drug required to reduce phosphorylation of the adaptor protein p-Crkl by 50%) to imatinib, dasatinib, and nilotinib, regardless of which TKI was used to induce resistance. This suggests that currently available TKIs share the same susceptibilities to drug resistance.

Original languageEnglish
Pages (from-to)2139-2147
Number of pages9
JournalLeukemia and Lymphoma
Volume52
Issue number11
DOIs
Publication statusPublished - 1 Nov 2011

Keywords

  • Cell lines and animal models
  • Drug resistance
  • Myeloid leukemias and dysplasias

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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