title: Adaptive responses to antibody based therapy.
abstract: Receptor tyrosine kinases (RTKs) represent a large class of protein kinases that span the cellular membrane. There are 58 human RTKs identified which are grouped into 20 distinct families based upon their ligand binding, sequence homology and structure. They are controlled by ligand binding which activates intrinsic tyrosine-kinase activity. This activity leads to the phosphorylation of distinct tyrosines on the cytoplasmic tail, leading to the activation of cell signaling cascades. These signaling cascades ultimately regulate cellular proliferation, apoptosis, migration, survival and homeostasis of the cell. The vast majority of RTKs have been directly tied to the etiology and progression of cancer. Thus, using antibodies to target RTKs as a cancer therapeutic strategy has been intensely pursued. Although antibodies against the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) have shown promise in the clinical arena, the development of both intrinsic and acquired resistance to antibody-based therapies is now well appreciated. In this review we provide an overview of the RTK family, the biology of EGFR and HER2, as well as an in-depth review of the adaptive responses undertaken by cells in response to antibody based therapies directed against these receptors. A greater understanding of these mechanisms and their relevance in human models will lead to molecular insights in overcoming and circumventing resistance to antibody based therapy.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, WIMR 3136, Madison, WI 53705, USA. Electronic address: rodems@wisc.edu.
authors.forename: Tamara S
authors.initials: TS
authors.lastname: Rodems
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, WIMR 3136, Madison, WI 53705, USA. Electronic address: iida@humonc.wisc.edu.
authors.forename: Mari
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, WIMR 3136, Madison, WI 53705, USA. Electronic address: tmbrand@wisc.edu.
authors.forename: Toni M
authors.initials: TM
authors.lastname: Brand
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, WIMR 3136, Madison, WI 53705, USA. Electronic address: hepearson@wisc.edu.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Pearson
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, WIMR 3136, Madison, WI 53705, USA. Electronic address: rorbuch@wisc.edu.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Orbuch
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, WIMR 3136, Madison, WI 53705, USA. Electronic address: bgflanigan@wisc.edu.
authors.forename: Bailey G
authors.initials: BG
authors.lastname: Flanigan
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, WIMR 3136, Madison, WI 53705, USA. Electronic address: dlwheeler@wisc.edu.
authors.forename: Deric L
authors.initials: DL
authors.lastname: Wheeler
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D000906:Antibodies; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: Antibodies; EGFR; HER2; MET; Receptor tyrosine kinases; Therapeutic resistance