Loss of SYK and LYN Tyrosine Kinase Expression Impair Ponatinib-Induced Apoptosis in K562 Cells

Authors

  • Valérie Lagarde Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux
  • François-Xavier Mahon Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux
  • Jean-Max Pasquet Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux

Keywords:

Chronic myeloid leukemia, Drug resistance, BCR-ABL, Tyrosine kinase inhibitors, Kinase

Abstract

Targeting the tyrosine kinase activity of BCR-ABL is the gold standard strategy in Chronic Myeloid Leukemia (CML) for the last decade. Whereas inhibitors of BCR-ABL tyrosine kinase are now used in frontline therapy for CML, third generation inhibitors of BCR-ABL tyrosine kinase such as ponatinib has been developed for the treatment of BCR-ABL resistant mutants. In the current study, we generated K562 ponatinib resistant cells (KRPO) and investigated its mechanism of resistance. No over expression of BCR-ABL or multidrug resistance gene (MDR-1) were found among the investigated mechanisms as verapamil did not overcome resistance. Downregulated expression of both p72 SYK and p53/56 LYN kinases was found in ponatinib K562 resistant cell line. Albeit both mRNA and protein level were decreased in KRPO for SYK only protein level was downregulated for LYN suggesting a posttranscriptional mechanism. This mechanism of resistance also prevents imatinib, nilotinib or dasatinib-induced CML cells apoptosis.

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Published

2015-12-31

Issue

Vol. 2 (2015)

Section

Articles

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