Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606

• Published in: Blood Vol. 111; no. 4; pp. 2329 - 2338
• Main Authors: Konig, Heiko, Holyoake, Tessa L., Bhatia, Ravi
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-02-2008; The Americain Society of Hematology; American Society of Hematology
• Series: Neoplasia
• Subjects: Aniline Compounds - pharmacology; Antineoplastic Agents - therapeutic use; Benzamides; Biological and medical sciences; Fetal Blood - cytology; Fetal Blood - drug effects; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - pathology; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Neoplasia; Nitriles - pharmacology; Piperazines - therapeutic use; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-abl - antagonists & inhibitors; Pyrimidines - therapeutic use; Quinolines - pharmacology; src-Family Kinases - antagonists & inhibitors; Hematology; Enzyme; Transferases; Stem cell; Hematopoietic cell; Chronic myelogenous leukemia; Malignant hemopathy; Myeloproliferative syndrome; Primitive; Efficiency; Kinase; C-Onc gene; Inhibitor; Protein-tyrosine kinase; Protooncogene; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-05-092056

Imatinib mesylate (imatinib) is highly effective in the treatment of chronic myeloid leukemia (CML) but is less effective in eliminating CML stem cells. We investigated whether SKI-606, a potent Bcr-Abl and Src kinase inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors. CML and normal progenitors were cultured with SKI-606 or imatinib. SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34+ cells and inhibited Src phosphorylation more potently than imatinib. However, SKI-606 and imatinib resulted in similar suppression of CML primitive and committed progenitor proliferation and growth in CFC and LTC-IC assays. Exposure to either agent alone or in combination resulted in only modest increase in apoptosis. Evaluation of downstream signaling pathways indicated that Akt and STAT5 activity was not changed, but a delayed increase in MAPK activity was seen at high concentrations of SKI-606. SKI-606 inhibited normal progenitor proliferation to a lesser extent than imatinib. SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors. However, SKI-606 does not demonstrate increased ability to eliminate primitive CML progenitors by apoptosis compared with imatinib, emphasizing the need for additional strategies besides Bcr-Abl kinase inhibition for curative therapy of CML.