|Journal of Translational Proteomics Research (Volume 2)|
|Loss of SYK and LYN Tyrosine Kinase Expression Impair Ponatinib-Induced Apoptosis in K562 Cells|
Valérie Lagarde, François-Xavier Mahon and Jean-Max PasquetDOI: http://dx.doi.org/10.15379/2410-3802.2015.02.3
Published: 31 December 2015
|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.
|Chronic myeloid leukemia, Drug resistance, BCR-ABL, Tyrosine kinase inhibitors, Kinase.|