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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-01-0288.
Submitted January 30, 2002
Accepted August 21, 2002
Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing STI571 resistant Bcr/Abl kinases
Markus Warmuth, Nicola Simon, Olga Mitina, Ruth Mathes, Doriano Fabbro, Paul W Manley, Elisabeth Buchdunger, Karin Forster, Ismail Moarefi, and Michael Hallek*
CCG Gene Therapy, GSF-National Research Institute for Environment and Health, Muenchen, Germany; Department of Internal Medicine III, University of Muenchen, Muenchen, Germany
CCG Gene Therapy, GSF-National Research Institute for Environment and Health, Muenchen, Germany
Oncology Research, Novartis Pharma AG, Basel, Switzerland
Max-Planck-Institute for Biochemistry, Martinsried, Germany
CCG Gene Therapy, GSF-National Research Institute for Environment and Health, Muenchen, Germany; Department of Internal Medicine III, University of Muenchen, Muenchen, Germany; Gene Center, University of Muenchen, Muenchen, Germany
* Corresponding author; email: mhallek{at}med3.med.uni-muenchen.de.
The leukemogenic tyrosine kinase Bcr-Abl contains a highly conserved inhibitor binding pocket (IBP), which serves as a binding site for STI571. Mutations at the IBP may lead to resistance of the Abl kinase against STI571. To examine the mechanisms of STI571 binding and resistance in more detail, we created several point mutations at amino acid positions 315 and 380 of Abl, blocking the access to the IBP and rendering Bcr-Abl STI571 resistant. Moreover, introduction of a mutation destabilizing the inactive conformation of Abl (D276S/E279S) also lead to STI571 resistance, suggesting that the inhibitor required inactivation of the kinase prior to binding. These Bcr-Abl mutants were then used to evaluate the binding mode and specificity of two compounds, PP1 and CGP76030, originally characterized as Src kinases inhibitors. Both compounds inhibited Bcr-Abl in a concentration dependent manner by overlapping binding modes. However, in contrast to STI571, PP1 and CGP76030 blocked cell growth and survival in cells expressing various inhibitor resistant Abl mutants. Studies on the potential signaling mechanisms demonstrated that in cells expressing inhibitor resistant Bcr-Abl mutants PP1 and CGP76030 inhibited the activity of Src family tyrosine kinases and Akt but not STAT5 and Jnk. The results suggest that the use of Src kinase inhibitors is a potential strategy to prevent or overcome clonal evolution of STI571 resistance in Bcr/Abl positive leukemia.
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