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.