ERBB receptors and their cognate ligands provide a rich and complex multilayered network of signaling control. Multiple layers of control act to safeguard against unwanted ERBB receptor activation, including the "closed" conformations of ligand-unbound EGFR, ERBB3, and ERBB4, auto-inhibited interactions among "open" conformation extracellular domains (ECDs), a vast repertoire of receptor-specific ligands (with, in some cases, a myriad of isoforms), the potential to form high-order complexes with associated proxy phosphorylation, and receptor-mediated endocytosis with associated recycling and degradation pathways. Despite these extensive safeguards, the deregulation of ERBB receptors is observed in multiple tumor types. In the case of ERBB2, the use of therapeutic antibodies aimed at distinct epitopes within the extracellular domain has resulted in marked improvements in clinical efficacy, and greater understanding of biology of ERBB2 receptor trafficking following receptor-mediated endocytosis has led to important insights in the development of an antibody-drug conjugate targeting this receptor. The multilayered nature of ERBB signaling offers a broad spectrum of future points for consideration of therapeutic interventions.
- Pathological complete response
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