Adaptive responses to antibody based therapy

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• 作者：Tamara S. Rodems ^{rodems@wisc.edu" class="auth_mail" title="E-mail the corresponding author} ; Mari Iida ^{iida@humonc.wisc.edu" class="auth_mail" title="E-mail the corresponding author} ; Toni M. Brand ^{tmbrand@wisc.edu" class="auth_mail" title="E-mail the corresponding author} ; Hannah E. Pearson ^{hepearson@wisc.edu" class="auth_mail" title="E-mail the corresponding author} ; Rachel A. Orbuch ^{rorbuch@wisc.edu" class="auth_mail" title="E-mail the corresponding author} ; Bailey G. Flanigan ^{bgflanigan@wisc.edu" class="auth_mail" title="E-mail the corresponding author} ; Deric L. Wheeler ; ^{dlwheeler@wisc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CBL ; casitas B-lineage lymphoma ; CtxR ; cetuximab-resistant ; CtxS ; cetuximab-sensitive ; CRC ; colorectal cancer ; EGF ; epidermal growth factor ; EGFR ; epidermal growth factor receptor ; EMT ; epithelial to mesenchymal transition ; EPR ; epiregulin ; FDA ; food and drug administration ; HB-EGF ; heparin-binding epidermal growth factor ; HER2 ; human epidermal growth factor receptor 2 ; HER3 ; human epidermal growth factor receptor 3 ; HNSCC ; head and neck squamous cell carcinoma ; IGF-1R ; insulin-like growth facto
• 刊名：Seminars in Cell & Developmental Biology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：50
• 期：Complete
• 页码：153-163
• 全文大小：1065 K

文摘

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, apopotosis, 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.