CO45 Impact of Smoking Status on the Combination of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors and Antiangiogenic Agents in Advanced Non-Small-Cell Lung Cancer Harbored Susceptible EGFR Mutation: A Systematic Review and Meta-Analysis
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Epidermal growth factor receptor (EGFR) and its three related proteins (the ERBB family) are receptor tyrosine kinases that play essential roles in both normal physiological conditions and cancerous conditions. Upon binding its ligands, dynamic conformational changes occur in both extracellular and intracellular domains of the receptor tyrosine kinases, resulting in the transphosphorylation of tyrosine residues in the C-terminal regulatory domain. These provide docking sites for downstream molecules and lead to the evasion of apoptosis, to proliferation, to invasion and to metastases, all of which are important for the cancer phenotype. Mutation in the tyrosine kinase domain of the EGFR gene was found in a subset of lung cancers in 2002. Lung cancers with an EGFR mutation are highly sensitive to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib. Here, we review the discovery of EGFR, the EGFR signal transduction pathway and mutations of the EGFR gene in lung cancers and glioblastomas. The biological significance of such mutations and their relationship with other activated genes in lung cancers are also discussed.
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Pancreatic cancer is one of the most fatal among all solid malignancies. Targeted therapeutic approaches have the potential to transform cancer therapy as exemplified by the success of several tyrosine kinase inhibitors. Prompted by this, comprehensive profiling of tyrosine kinases and their substrates was carried out using a panel of low passage pancreatic cancer cell lines. One of the pancreatic cancer cell lines, P196, which showed dramatic upregulation of tyrosine kinase activity as compared to non-neoplastic cells, was systematically studied using a quantitative proteomic approach called stable isotope labeling with amino acids in cell culture (SILAC). A careful analysis of activated tyrosine kinase pathways revealed aberrant activation of epidermal growth factor receptor pathway in this cell line. Mouse xenograft based studies using EGFR inhibitor erlotinib confirmed EGFR pathway to be responsible for proliferation in these tumors. By a systematic study across low passage pancreatic cancer cell lines and mice carrying pancreatic cancer xenografts, we have demonstrated activated epidermal growth factor receptor as an attractive candidate for targeted therapy in a subset of pancreatic cancers. Further, we propose immunohistochemical labeling of activated EGFR (pEGFR1068) as an efficient screening tool to select patients who are more likely to respond to EGFR inhibitors.
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Epidermal growth factor receptor (EGFR) tyrosine kinase is over-expressed in numerous human tumors, which plays pivotal roles in cellular signal transduction, and it is involved in a variety of tumor cellular behaviors such as proliferation, metastasis, angiogenesis and so on. Many investigations have indicated that tumor growth can be suppressed by inhibiting EGFR tyrosine kinase activity. Currently, several EGFR tyrosine kinase inhibitors are in clinical trial stage.
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Abstract: MET receptor tyrosine kinase and its natural ligand, hepatocyte growth factor, have been implicated in a variety of cancers, including non-small cell lung cancer (NSCLC). Mechanisms by which cellular deregulation of MET occurs include overexpression, genomic amplification, mutation, or alternative splicing. MET overexpression or activation is a known cause of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in NSCLC. Inhibition of MET signaling in these EGFR tyrosine kinase inhibitor-resistant cells may potentially restore sensitivity to EGFR inhibitors. Tivantinib (ARQ 197), reported as a small-molecule MET inhibitor, has demonstrated antitumor activity in early clinical studies. This review focuses on MET and lung cancer, the clinical development of tivantinib, the clinical trials of tivantinib in NSCLC to date, its current/emerging role in the management of NSCLC, and future directions. Keywords: MET inhibitor, tivantinib, ARQ 197, non-small cell lung cancer © 2014 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License . By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms .
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Epidermal growth factor receptor is a trans-membrane glycoprotein with an extracellular epidermal growth factor binding domain and an intracellular tyrosine kinase domain that regulates signaling pathways to control cellular proliferation. Epidermal growth factor receptor binding to its ligand results in autophosphorylation by intrinsic tyrosine/kinase activity, triggering several signal transduction cascades. Constitutive or sustained activation of these sequences of downstream targets is thought to yield more aggressive tumor phenotypes. Mutations in epidermal growth factor receptor have been discovered in association with some lung cancers. Lung adenocarcinomas with mutated epidermal growth factor receptor have significant responses to tyrosine kinase inhibitors, although for unselected patients it does not appear to have a survival benefit. However, in a subset of patients (non-smoking Asian women with adenocarcinoma, particularly with a bronchioloalveolar carcinoma), there appears to be a significant survival advantage. Both EGFR mutation and gene amplification status may be important in determining which tumors will respond to tyrosine kinase inhibitors.
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The finding of epidermal growth factor receptor tyrosine kinase inhibitors, which reflects a classical process of translational research, is a critical milestone for non-small-cell lung cancer treatment. Currently, epidermal growth factor receptor tyrosine kinase inhibitors are recommended as first-line therapy for non-small-cell lung cancer patients harboring epidermal growth factor receptor–sensitive mutations. The status of epidermal growth factor receptor mutation is widely acknowledged as superior to other clinical factors, such as smoking, gender, and histological types for predicting the response to epidermal growth factor receptor tyrosine kinase inhibitors. However, recent studies have shown that the efficacy might differ in patients with the same epidermal growth factor receptor–sensitive mutations, highlighting the need to investigate the putative factors related to the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors. This article reviews the factors associated with clinical efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib and erlotinib, and analyzes their potential implications with respect to clinical application. In addition, new findings related to clinical practice with respect to epidermal growth factor receptor tyrosine kinase inhibitors efficacy were summarized in this article.
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Canine mammary gland tumours (CMTs) are the most common malignancies in female dogs. The receptor tyrosine kinase EGFR (erbb1), a receptor for epidermal growth factor (EGF) and related factors, mediates multiple oncogenic functions in human epithelial neoplasms. While previous studies have demonstrated EGFR expression in canine tumours, its function has not been studied in canine cancer. The purpose of this study was to determine the in vitro effects of EGF and vandetanib (ZD6474), a small molecule inhibitor of VEGFR‐2, EGFR and RET tyrosine kinases, on proliferation, invasion, survival and chemosensitivity in CMT cells. In low serum, EGF enhanced proliferation and chemotaxis, attenuated apoptosis, and stimulated vascular endothelial growth factor (VEGF) production. Vandetanib dose‐dependently inhibited EGFR phosphorylation as well as PI3K/Akt activation, and inhibited all EGF‐induced phenotypic effects. In conclusion, EGF stimulates multiple features promoting the malignant phenotype in CMT. Thus, CMT may be an important translational model for the investigation of novel EGFR‐directed therapies.
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The signal transduction system induced by epidermal growth factor receptor(EGFR) regulates cell cycle ,modulates cell growth and differentiation and improves damage repair.The overexpression of EGFR in several epithelial tumors including non small cell lung cancer(NSCLC) forecasts low survival rate, poor prognosis and metastasis. Thereby EGFR can be a potential target for gene therapy. Tyrosine kinase inhibitors(TKIs) selectively inhibit tyrosine kinase activity,supress tumor growth ,and increase the sensitivity of radio chemotherapy. [
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Epidermal growth factor receptor (EGFR), also known as ERBB, ERBB1, HER1, NISBD2, PIG61, and mENA, is a transmembrane glycoprotein with an intracellular tyrosine kinase that serves as a receptor for extracellular protein ligands. EGFR was the first member of the ErbB receptor family to be described. The ErbB receptors are a subfamily of four tyrosine kinase receptors including EGFR, HER-2/neu, HER-3, and HER-4. Ten different ligands can selectively bind to each receptor, and ligand binding leads to downstream pathways involved in cellular growth and proliferation as well as differentiation.EGFR overexpression is involved in multiple tumors and is associated with neurodegenerative diseases such as Alzheimer disease. The pathologies associated with EGFRs have led to novel treatment modalities, including monoclonal antibodies designed to inhibit EGFR signaling.
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Receptor tyrosine kinases (RTKs) are a superfamily of transmembrane proteins that mediate intracellular signaling by phosphorylating substrate proteins involved in cell proliferation, survival, differentiation or migration. The Human Epidermal growth factor Receptor (HER) family belongs to the RTKs superfamily, and comprises four members: EGFR (epidermal growth factor receptor), HER2, HER3 and HER4. Physiologically, these receptors are activated by the ligands of the EGF family. In solid tumors other mechanisms of activation, such as overexpression or molecular alterations have been reported, and have been linked to tumour initiation/progression. Because of that, several strategies have been developed to target HER receptors and include i) antibody-based therapies using monoclonal antibodies against the extracellular domain of these receptors, and ii) small molecule tyrosine kinase inhibitors (TKIs) against the intracellular kinase domain. In this review we will provide basic information about biological aspects of HER receptors and their ligands as well as the therapeutic strategies to target them. We also summarize general mechanisms of resistance generated in patients to such anti-HER therapies.
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