title: Nimotuzumab and cetuximab block ligand-independent EGF receptor signaling efficiently at different concentrations.
abstract: The epidermal growth factor receptor (EGFR) is overexpressed in several epithelial tumors such as breast, ovarian, and colon cancers. Nimotuzumab and Cetuximab are antibodies that inhibit ligand binding upon interaction with the EGFR, thereby indirectly inactivating the EGFR kinase. The ability of an antibody to counteract growth depends on its mechanism of action as well as on its binding affinity. Nimotuzumab has lower binding affinity for the EGFR than does Cetuximab. In addition, a mechanistic difference has recently been suggested to explain the different clinical effects of Nimotuzumab and Cetuximab, arguing that Nimotuzumab partly permits kinase activity and downstream signaling under conditions where binding of EGF is inhibited. We have in the current study compared the effects of Nimotuzumab and Cetuximab on binding of EGF as well as on inhibition of constitutive EGFR-ErbB2 dimerization and downstream activation of Erk. Our results demonstrate that (at least in EGFR-overexpressing cells), in contrast to the recently published mechanistic model, Nimotuzumab not only inhibits EGF-stimulated, but also ligand-independent (basal) signaling although at higher concentrations than required with Cetuximab.
authors.affiliation: Institute of Pathology, Faculty of Medicine, University of Oslo, Blindern, Norway.
authors.forename: Christian
authors.initials: C
authors.lastname: Berger
authors.forename: Ute
authors.initials: U
authors.lastname: Krengel
authors.forename: Espen
authors.initials: E
authors.lastname: Stang
authors.forename: Ernesto
authors.initials: E
authors.lastname: Moreno
authors.forename: Inger Helene
authors.initials: IH
authors.lastname: Madshus
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000276:immunology; D055503:Protein Multimerization / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C501466:nimotuzumab