Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib.
Imatinib is a tyrosine kinase inhibitor that suppresses the growth of bcr-abl-expressing chronic myeloid leukemia (CML) progenitor cells by blockade of the adenosine triphosphate (ATP)-binding site of the kinase domain of bcr-abl. Imatinib also inhibits the c-abl, platelet-derived growth factor (PDGF) receptor, abl-related gene (ARG) and stem-cell factor (SCF) receptor tyrosine kinases, and has been used clinically to inhibit the growth of malignant cells in patients with CML and gastrointestinal stromal tumors (GISTs). Although initially considered to have minimal effects of normal hematopoiesis, recent studies show that imatinib also inhibits the growth of some nonmalignant hematopoietic cells, including monocyte/macrophages. This inhibition could not be attributed to the known activity profile of imatinib. Here, we demonstrate for the first time that imatinib targets the macrophage colony-stimulating factor (M-CSF) receptor c-fms. Phosphorylation of c-fms was inhibited by therapeutic concentrations of imatinib, and this was not due to down-regulation in c-fms expression. Imatinib was also found to inhibit M-CSF-induced proliferation of a cytokine-dependent cell line, further supporting the hypothesis that imatinib affects the growth and development of monocyte and/or macrophages through inhibition of c-fms signaling. Importantly, these results identify an additional biologic target to those already defined for imatinib. Imatinib should now be assessed for activity in diseases where c-fms activation is implicated, including breast and ovarian cancer and inflammatory conditions.
Dewar
Andrea L
AL
Division of Haematology, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia. andrea.dewar@imvs.sa.gov.au
Cambareri
Antony C
AC
Zannettino
Andrew C W
AC
Miller
Bernadette L
BL
Doherty
Kathleen V
KV
Hughes
Timothy P
TP
Lyons
A Bruce
AB
D000906:Antibodies / Q000494:pharmacology; D001549:Benzamides; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D008264:Macrophages / Q000166:cytology; D009000:Monocytes / Q000166:cytology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000906:Antibodies; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016186:Receptor, Macrophage Colony-Stimulating Factor