Destabilization of Bcr-Abl/Jak2 Network by a Jak2/Abl Kinase Inhibitor ON044580 Overcomes Drug Resistance in Blast Crisis Chronic Myelogenous Leukemia (CML)

摘要: Bcr-Abl is the predominant therapeutic target in chronic myeloid leukemia (CML), and tyrosine kinase inhibitors (TKIs) that inhibit have been successful treating CML. With progression of CML disease especially blast crisis stage, cells from patients become resistant to imatinib mesylate (IM) other TKIs, resulting relapse. Because known drive multiple signaling pathways, study regulation stability IM-resistant a critical issue as possible strategy. Here, we report new dual-kinase chemical inhibitor, ON044580, induced apoptosis Bcr-Abl+ IM-sensitive, cells, including gatekeeper mutant, T315I, also patients. In addition, K562-R patients, all cell lines tested had reduced ability form colonies soft agar presence 0.5 µM ON044580. vitro assays, ON044580 inhibited recombinant Jak2 Abl activities when respective peptides were used substrates. Incubation with rapidly levels protein expression HSP90 its client levels. Lysates found contain large network complex composed Bcr-Abl, Jak2, HSP90, proteins detected by gel filtration column chromatography, which was disrupted Therefore, targeting kinases an effective way destabilize complex, leads onset IM-sensitive cells. This inhibitory strategy has potential manage types drug-resistant at terminal stage CML, where TKIs are not clinically useful.