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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-01-0288.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 664-672
NEOPLASIA
Dual-specific Src and Abl kinase inhibitors, PP1 and
CGP76030, inhibit growth and survival of cells expressing imatinib
mesylate-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
From the Klinische Kooperationsgruppe für
Gentherapie, GSF Forschungszentrum für Umwelt und
Gesundheit, Munich, Germany; Medizinische Klinik III, Klinikum der
Ludwig-Maximilians-Universität München, Munich, Germany;
Novartis Pharma, Oncology Research, Basel, Switzerland;
Max-Planck-Institute for Biochemistry, Martinsried, Germany; and
Genzentrum, Ludwig-Maximilians- Universität München,
Munich, Germany.
The leukemogenic tyrosine kinase Bcr-Abl contains a highly
conserved inhibitor-binding pocket (IBP), which serves as a
binding site for imatinib mesylate. Mutations at the IBP may lead
to resistance of the Abl kinase against imatinib mesylate. To examine
the mechanisms of imatinib mesylate 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 imatinib mesylate-resistant. Moreover, introduction of a mutation destabilizing the inactive conformation of Abl (Asp276Ser/Glu279Ser) also led to imatinib mesylate 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 2 compounds, PP1 and CGP76030, originally
characterized as Src kinase inhibitors. Both compounds
inhibited Bcr-Abl in a concentration-dependent manner by overlapping
binding modes. However, in contrast to imatinib mesylate, 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 signal
transducer and activator of transcription-5 (STAT5) and JUN
kinase (Jnk). The results suggest that the use of Src kinase
inhibitors is a potential strategy to prevent or overcome clonal
evolution of imatinib mesylate resistance in
Bcr-Abl+ leukemia.
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