Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells

Abstract

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.

Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells

“…Alternatively, Johnson et al reported the activation of EGFR in imatinibtreated squamous carcinoma cells leading to increased activity of downstream ERK signaling (32). In our study, phospho-VEGFR was undetected by Western blotting and the activation of EGFR was not found in the imatinib-treated glioma cells (data not shown).…”

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

“…However, direct therapeutic targeting of tumor-promoting transcription factors, for example, by small molecule inhibitors is difficult. Our findings linking the proinvasive transcription factor CUTL1 and the Src pathway provide not only important new insights in the molecular effector pathways mediating CUTL-induced migration and invasion but also suggest that CUTL1-positive tumors such as highly invasive pancreatic or breast cancers might be particularly susceptible to small molecule inhibitors targeting Src tyrosine kinases, which are currently in preclinical and clinical evaluation (Johnson et al, 2005). Further studies are warranted to elucidate the clinical significance of Src activation in CUTL1-positive tumors and its potential applicability for therapeutic targeting.…”

Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non–Small Cell Lung Cancer Cells

“…Although dasatinib also inhibits c-kit, Abl, and PDGFR, we believe that it is unlikely that dasatinib mediates a significant effect on cell cycle progression or apoptosis, because such effects were not seen in these same cells lines treated with imatinib at doses in excess of those needed to inhibit these kinases (5 Amol/L; refs. 40,41). Another possible therapeutic target is EphA2, the expression of which correlates with an advanced stage and poor prognosis in NSCLC (42).…”