bms-911543 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Imatinib Mesylate (IM) and other tyrosine kinase inhibitor (TKI) therapies have had a major impact on the treatment of chronic myeloid leukemia (CML). However, TKI monotherapy is not curative, with relapse and persistence of leukemic stem cells (LSCs) remaining a challenge. We have recently identified an AHI-1-BCR-ABL-JAK2 protein complex that contributes to the transforming activity of BCR-ABL and IM-resistance in CML stem/progenitor cells. JAK2 thus emerges as an attractive target for improved therapies, but off-target effects of newly developed JAK2 inhibitors on normal hematopoietic cells remain a concern. We have examined the biological effects of a highly selective, orally bioavailable JAK2 inhibitor, BMS-911543, in combination with TKIs on CD34+ treatment-naïve IM-nonresponder cells. Combination therapy reduces JAK2/STAT5 and CRKL activities, induces apoptosis, inhibits proliferation and colony growth, and eliminates CML LSCs in vitro. Importantly, BMS-911543 selectively targets CML stem/progenitor cells while sparing healthy stem/progenitor cells. Oral BMS-911543 combined with the potent TKI dasatinib more effectively eliminates infiltrated leukemic cells in hematopoietic tissues than TKI monotherapy and enhances survival of leukemic mice. Dual targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may consequently lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Cell Proliferation; Dasatinib; Drug Resistance, Neoplasm; Heterocyclic Compounds, 3-Ring; Humans; Imatinib Mesylate; Janus Kinase 2; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neoplastic Stem Cells; Nuclear Proteins; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Pyrimidines; Signal Transduction; STAT5 Transcription Factor; Thiazoles; Time Factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays