text: Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells.
  Imatinib mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients.
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entities.type: CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-N GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y CHEMICAL GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
entities.text: Imatinib imatinib imatinib imatinib mesylate kinase PDGFR EGFR heparin-binding epidermal growth factor-like growth factor c-kit HB-EGF Imatinib mesylate kinases transforming growth factor-alpha mitogen activated protein kinase MAPK HB-EGF HB-EGF BCR MAPK ABL EGFR imatinib c-kit EGFR tyrosine kinases EGFR tyrosine kinase tyrosine kinase epidermal growth factor receptor EGFR ABL EGFR Imatinib platelet-derived growth factor receptor EGFR EGFR mitogen-activated protein/extracellular signal-regulated kinase kinase 1 MEK1 EGFR Her2 ErbB2 kinase EGFR imatinib heparin-binding EGF-like growth factor EGF receptor imatinib tyrosine tyrosine imatinib imatinib