EGFR blockade by tyrosine kinase inhibitor or monoclonal antibody inhibits growth, directs terminal differentiation and induces apoptosis in the human squamous cell carcinoma HN5.
Human squamous cell carcinomas frequently overexpress the epidermal growth factor receptor (EGFR) and this is often associated with poor prognosis in patients with these cancers. The high level of expression of the EGFR provides an important target for therapy and we and others have shown that monoclonal antibodies (mAbs) which block the activation of the receptor by the EGF family of ligands inhibit the growth of EGFR overexpressing tumours in vitro and induce the regression of established tumours grown as xenografts in athymic mice. Inhibitors of the tyrosine kinase associated with the EGFR have also been shown to block receptor activation and prevent tumour cell proliferation. Using the EGFR-overexpressing head and neck carcinoma cell line HN5, we have compared the biological consequences of treatment with an inhibitor of EGFR tyrosine kinase (PD153035) with anti-EGFR monoclonal antibodies (mAbs) ICR63 or ICR80. We found that both the anti-EGFR mAbs and the TK inhibitor produce similar biological changes namely, they inhibit the EGF and TGFá-induced tyrosine phosphorylation of the receptor and the growth in culture of HN5 cells. At concentrations above 100 nM, the TK inhibitor prevented the growth in culture of HN5 cells completely with an IC50 of 40 nM. With the anti-EGFR mAbs, growth of HN5 cells was inhibited completely at concentrations above 4 nM with an IC50 of 1 nM. More importantly we found that, like the anti-EGFR mAbs, treatment with the TK inhibitor directs HN5 cells to undergo terminal differentiation as monitored by the expression of cytokeratin 10. In addition, our results indicate that the growth inhibitory effects of the anti-EGFR agents also lead to induction of apoptosis as determined by 7-amino actinomycin D staining (7-AAD). We conclude that EGFR blockade by anti-EGFR mAbs or TK inhibitor influences the growth in culture of EGFR overexpressing tumours by directing terminal differentiation and inducing apoptosis.
The Institute of Cancer Research, McElwain Laboratories, Belmont, Sutton, Surrey, UK.
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Modjtahedi
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Affleck
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Stubberfield
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Dean
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D011799:Quinazolines; D014443:Tyrosine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline