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Indian Journal of Dental Research :... 2017Cells are constantly exposed to various external stimuli which regulate the growth and survival of the cells. The signal transduction from the external environment to... (Review)
Review
Cells are constantly exposed to various external stimuli which regulate the growth and survival of the cells. The signal transduction from the external environment to the interior of the cell is carried out by cell surface or transmembrane receptors. Epidermal growth factor receptor (EGFR) is a type I receptor tyrosine kinase and along with its ligands, EGFR is involved in the regulation of multiple cellular pathways. EGFR and its signaling pathway have been studied extensively for the biological and pathophysiological role in health and disease. There is enough evidence to suggest that EGFR is involved in the pathogenesis and progression of various cancers. This review discusses the structural anatomy and physiology of EGFR and its ligands, the role of EGFR in cancer and EGFR-targeted therapy.
Topics: ErbB Receptors; Head and Neck Neoplasms; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 29256471
DOI: 10.4103/ijdr.IJDR_534_16 -
Annals of Oncology : Official Journal... Dec 1997The epidermal growth factor receptor (EGFR) is a growth factor receptor that induces cell differentiation and proliferation upon activation through the binding of one of... (Review)
Review
The epidermal growth factor receptor (EGFR) is a growth factor receptor that induces cell differentiation and proliferation upon activation through the binding of one of its ligands. The receptor is located at the cell surface, where the binding of a ligand activates a tyrosine kinase in the intracellular region of the receptor. This tyrosine kinase phosphorylates a number of intracellular substrates that activates pathways leading to cell growth, DNA synthesis and the expression of oncogenes such as fos and jun. EGFR is thought to be involved the development of cancer, as the EGFR gene is often amplified, and/or mutated in cancer cells. In this review we will focus on: (I) the structure and function of EGFR, (II) implications of receptor/ligand coexpression and EGFR mutations or overexpression, (III) its effect on cancer cells, (IV) the development of the malignant phenotype and (V) the clinical aspects of therapeutic targeting of EGFR.
Topics: Clinical Trials as Topic; ErbB Receptors; Gene Deletion; Humans; Mutation; Neoplasms; Phenotype; Signal Transduction
PubMed: 9496384
DOI: 10.1023/a:1008209720526 -
Cancer Cell Mar 2014ERBB receptors were linked to human cancer pathogenesis approximately three decades ago. Biomedical investigators have since developed substantial understanding of the... (Review)
Review
ERBB receptors were linked to human cancer pathogenesis approximately three decades ago. Biomedical investigators have since developed substantial understanding of the biology underlying the dependence of cancers on aberrant ERBB receptor signaling. An array of cancer-associated genetic alterations in ERBB receptors has also been identified. These findings have led to the discovery and development of mechanism-based therapies targeting ERBB receptors that have improved outcome for many cancer patients. In this Perspective, we discuss current paradigms of targeting ERBB receptors with cancer therapeutics and our understanding of mechanisms of action and resistance to these drugs. As current strategies still have limitations, we also discuss challenges and opportunities that lie ahead as basic scientists and clinical investigators work toward more breakthroughs.
Topics: Animals; Antibodies, Monoclonal, Humanized; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Mice; Neoplasms; Receptor, ErbB-2; Receptor, ErbB-3; Receptor, ErbB-4; Signal Transduction
PubMed: 24651011
DOI: 10.1016/j.ccr.2014.02.025 -
Trends in Cell Biology Jan 2014The ligand-stimulated epidermal growth factor receptor (EGFR) has been extensively studied in the analysis of molecular mechanisms regulating endocytic traffic and the... (Review)
Review
The ligand-stimulated epidermal growth factor receptor (EGFR) has been extensively studied in the analysis of molecular mechanisms regulating endocytic traffic and the role of that traffic in signal transduction. Although such studies have largely focused on mitogenic signaling and dysregulated traffic in tumorigenesis, there is growing interest in the potential role of EGFR traffic in cell survival and the consequent response to cancer therapy. Here we review recent advances in our understanding of molecular mechanisms regulating ligand-stimulated EGFR activation, internalization, and post-endocytic sorting. The role of EGFR overexpression/mutation and new modulators of EGFR traffic in cancer and the response to cancer therapeutics are also discussed. Finally, we speculate on the relationship between EGFR traffic and cell survival.
Topics: Animals; Antineoplastic Agents; Endocytosis; ErbB Receptors; GRB2 Adaptor Protein; Humans; Multivesicular Bodies; Mutation; Neoplasms; Protein Transport; Proteolysis; Signal Transduction; Ubiquitination
PubMed: 24295852
DOI: 10.1016/j.tcb.2013.11.002 -
The FEBS Journal Nov 2013The epidermal growth factor receptor (EGFR) is overexpressed in a variety of human epithelial tumors, often as a consequence of gene amplification. Tumors with EGFR gene... (Review)
Review
The epidermal growth factor receptor (EGFR) is overexpressed in a variety of human epithelial tumors, often as a consequence of gene amplification. Tumors with EGFR gene amplification frequently contain EGFR gene rearrangements, with the most common extracellular domain mutation being EGFRvIII. This mutation leads to a deletion of exons 2-7 of the EGFR gene and renders the mutant receptor incapable of binding any known ligand. Despite this, EGFRvIII displays low-level constitutive signaling that is augmented by reduced internalization and downregulation. Aberrant EGFRvIII signaling has been shown to be important in driving tumor progression and often correlates with poor prognosis. It is clear that EGFRvIII is expressed in a considerable proportion of patients with glioblastoma multiforme (GBM). The presence of EGFRvIII in other tumor types, however, remains controversial. In this review, we critically analyze the evidence for the expression of EGFRvIII in a range of tumor types and discuss recent findings pertinent to its function and biology in GBM.
Topics: Animals; ErbB Receptors; Gene Expression Regulation, Neoplastic; Humans; Neoplasms
PubMed: 23777544
DOI: 10.1111/febs.12393 -
Nature Medicine Nov 2013All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies... (Review)
Review
All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance.
Topics: Drug Resistance, Neoplasm; ErbB Receptors; Humans; Models, Biological; Molecular Targeted Therapy; Mutation; Neoplasms; Protein Kinase Inhibitors; Signal Transduction
PubMed: 24202392
DOI: 10.1038/nm.3388 -
Cell Nov 2007
Topics: ErbB Receptors; Models, Biological; Signal Transduction
PubMed: 18045542
DOI: 10.1016/j.cell.2007.11.013 -
Oncotarget Jul 2017Lung cancer is a leading cause of cancer mortality worldwide. In tumors, the important role of noncoding RNA regulatory networks has been more and more reveal. EGFR has... (Review)
Review
Lung cancer is a leading cause of cancer mortality worldwide. In tumors, the important role of noncoding RNA regulatory networks has been more and more reveal. EGFR has been identified as an oncogenic driver of NSCLC, especially activating mutations EGFR and its inhibition with specific TKIs can generate dramatic tumor responses. Studies have shown that EGFR plays significant roles in the progression of NSCLC. Subset analysis of the small proportion of patients with EGFR-mutant lung cancer showed a disease-free survival benefit, but was underpowered to detect a survival advantage. Herein, we highlight the progression of EGFR, noncoding RNA, and their roles in carcinogenesis. We also focus on anti-lung cancer drug development and EGFR-related drug resistance.
Topics: ErbB Receptors; Humans; Lung Neoplasms; Precision Medicine
PubMed: 28430586
DOI: 10.18632/oncotarget.16854 -
Molecules (Basel, Switzerland) Nov 2021Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts... (Review)
Review
Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.
Topics: Animals; Antineoplastic Agents; Binding, Competitive; Chemistry Techniques, Synthetic; Clinical Studies as Topic; Drug Approval; Drug Development; Drug Evaluation, Preclinical; ErbB Receptors; Humans; Ligands; Metabolic Networks and Pathways; Models, Molecular; Protein Binding; Protein Kinase Inhibitors; Structure-Activity Relationship
PubMed: 34771085
DOI: 10.3390/molecules26216677 -
Trends in Microbiology Nov 2017Members of the epidermal growth factor receptor family (ErbB family) possess a wide distribution and diverse functions ranging from cellular growth to migration and... (Review)
Review
Members of the epidermal growth factor receptor family (ErbB family) possess a wide distribution and diverse functions ranging from cellular growth to migration and apoptosis. Though highly implicated in a variety of cancers, their involvement in infectious disease is less recognised. A growing body of evidence now highlights the importance of the ErbB family in a variety of infections. Their role as growth factor receptors, along with other characteristics, such as surface expression and continuous intracellular trafficking, make this receptor family ideally placed for exploitation by pathogens. Herein, we review our current understanding of the role of the ErbB family in the context of infectious disease, exploring the mechanisms that govern pathogen exploitation of this system.
Topics: Adaptive Immunity; Animals; Carcinogenesis; Communicable Diseases; EGF Family of Proteins; ErbB Receptors; Host-Pathogen Interactions; Humans; Mice; Neoplasms
PubMed: 28522156
DOI: 10.1016/j.tim.2017.04.009