Targeted antireceptor therapy with monoclonal antibodies leads to the formation of inactivated tetrameric forms of ErbB receptors.
mAbs capable of disabling heterodimeric kinase complexes of the epidermal growth factor receptor (EGFR) and human EGFR type 2/neu have therapeutic relevance to various human cancers. In this study, we demonstrate that in addition to the dimer, EGFR and human EGFR type 2 can associate as homo- and heterotetramers. EGF-induced phosphorylation of the tetramers was significantly lower than that of the dimers, indicating that the tetrameric receptor complexes have impaired signaling activity. Targeting v-erb-b2 erythroblastic leukemia viral oncogene homolog (erbB) receptors with mAbs promoted erbB tetrameric assembly, suggesting that a component of the antitumor activity may be mediated by the ability of Abs to shift the equilibrium from active dimeric to impaired tetrameric receptor complex states. This study suggests a novel therapeutic approach to disable signaling of erbB and potentially other receptors in tumors by biologic agents capable of inducing receptor tetramerization.
Furuuchi
Keiji
K
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, 36th Hamilton Walk, Philadelphia, PA 19104, USA.
Berezov
Alan
A
Kumagai
Toru
T
Greene
Mark I
MI
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002384:Catalysis; D002460:Cell Line; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008970:Molecular Weight; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases