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Wild-type (wt)EGFR is amplified/overexpressed in a number of tumor types, and several mutant forms of the coding gene have been found, with ΔEGFR, a deletion mutation lacking exons 2–7 of the external domain, being the most common and particularly associated with glioblastoma. Dokduang H, Jamnongkarn W, Promraksa B, Suksawat M, Padthaisong S, Thanee M, Phetcharaburanin J, Namwat N, Sangkhamanon S, Titapun A, Khuntikeo N, Klanrit P, Loilome W. Drug Des Devel Ther. Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. The data from our tissue arrays support this finding and suggest that EGFR is highly expressed in ATC. In additional Western blot analyses, all of the cell lines were negative for the activated, or phosphorylated, form of EGFR (p-EGFR) unless stimulated with EGF (data not shown). For in vivo testing, gefitinib was dissolved in a lactate salt solution. The PCR was used to amplify exons 18, 19, and 21 from the EGFR gene using genomic DNA isolated from the following tumor-derived cell lines: papillary thyroid cancer cell line NPA187 and ATC cell lines DRO, K18, ARO, HTH-74, C643, and KAT-4. This showed that gefitinib at a dosage of 150 mg/kg/d can completely block expression of p-EGFR in a nude mouse model of thyroid carcinoma. Gefitinib partially blocked EGF autophosphorylation of EGFR at a concentration of 0.01 μmol/L and almost completely blocked autophosphorylation at 1 μmol/L. . Specimens from five of the six patients with ATC stained positive for EGFR; specimens from two of these five patients stained at level 2, whereas specimens from the three other patients stained at level 1. The mice treated with 150 mg/kg/QOD of gefitinib showed p-EGFR expression if euthanatized immediately before the final treatment was supposed to be given but did not express p-EGFR if euthanatized 6 hours after the final treatment, showing that a dosage of 150 mg/kg is unable to suppress EGFR phosphorylation for 48 hours. Enter multiple addresses on separate lines or separate them with commas. The vast majority of thyroid carcinomas are differentiated and can often be cured surgically. Gefitinib effectively blocks activation of EGFR by EGF, inhibits ATC cellular proliferation, and induces apoptosis in vitro. , 5) To determine the effect of inhibition of EGFR signaling on ATC cell proliferation in vitro, three MTT assays were performed using gefitinib at concentrations ranging from 1 to 20 μmol/L (Fig. Tumors were allowed to form, and after 1 month, the mice were euthanatized, and the tumors were subjected to immunohistochemical staining. The mice treated with gefitinib 150 mg/kg/d showed no expression of p-EGFR regardless of whether they were euthanatized 6 hours after the final treatment or immediately before the final treatment was scheduled, a fact that indicates that gefitinib at a dosage of 150 mg/kg/d is able to continuously suppress EGFR phosphorylation. eCollection 2020. and EGFR-mediated downstream signal transduction. Our data show that gefitinib at a daily dosage of 150 mg/kg is able to suppress EGFR activation for 24 to 48 hours in a nude mouse model of thyroid cancer. MiR-887-3p Negatively Regulates STARD13 and Promotes Pancreatic Cancer Progression. 2020 May 15;15(5):e0232985. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Whenever a discrepancy in scoring was noted, both pathologists reexamined the sample in question, and a consensus was reached. Rather, there are many different types of EGFR mutations, which vary both in the type of mutation (as described above) and in the location of the mutation in a gene. EGFR, which is encoded by the c-erb proto-oncogene, is a Mr 170,000 transmembrane cell-surface glycoprotein consisting of an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain with intrinsic tyrosine kinase activity (4 Activation of the EGF receptors EGFR (ErbB1) and HER2 (ErbB2) drives the progression of multiple cancer types through complex mechanisms that are still not fully understood. The epidermal growth factor receptor (EGFR) plays a pivotal role in colorectal carcinogenesis. * Killed immediately before treatment. Comparisons of ATC specimens with normal thyroid tissue specimens and ATC specimens with papillary thyroid cancer specimens revealed statistically significant differences in EGFR expression (P = 0.002 and P = 0.007, respectively). When treated at a concentration of 8 μmol/L (the IC50 for the MTT assays), 5.5% of the cells underwent apoptosis. The groups treated with gefitinib at dosages of 30, 60, 90, and 150 mg/kg/d had increased tumor sizes at day 12 of 158%, 165%, 112%, and 104% of the initial tumor size, respectively. The mice treated with gefitinib at 30 and 60 mg/kg/d showed high levels of p-EGFR. . An EGFR mutation does not refer to a single gene abnormality. The estimated IC50 for the apoptosis assays was 18.35 μmol/L. At a concentration of 12 μmol/L, 27.6% of the cells were apoptotic; at 19 μmol/L, 54.7%; at 22 μmol/L, 80.7%; and at 50 μmol/L, 94.5% (Fig. . Cells were plated at a density of 5 × 105 cells in 38 mm2 six-well plates (Costar, Cambridge, MA) and maintained for 24 hours before treatment with gefitinib. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. In this study, we report that HER2 expression is elevated in bone metastases of prostate cancer independently of gene amplification. In cancer, EGFR is often amplified, overexpressed, or mutated, resulting in abnormal signaling and malignant cellular behaviors; this dysregulation has a causal role in the development and maintenance of certain human carcinomas. Finally, gefitinib alone and in combination with paclitaxel was able to reduce the growth of ATC cells in a nude mouse model of thyroid carcinoma cells injected subcutaneously. All of the other mice then were placed into groups of five mice with similar average tumor volumes. Activation of EGFR by EGF was blocked by the addition of gefitinib. Photomontages were prepared using Adobe Photoshop software (Adobe Systems Inc., San Jose, CA). After the mice were euthanatized, the tumors again were measured, and the mice were weighed. Specimens from the mice treated with 90 mg/kg/d of gefitinib showed high levels of p-EGFR but did not stain as positively as did those from the mice treated with 30 or 60 mg/kg/d. The cancer tissue page shows antibody staining of the protein in 20 different cancers. Gefitinib is an EGFR tyrosine kinase inhibitor that has already been shown to have a favorable safety and tolerability profile in numerous Phase I clinical trials and therefore is a promising area of investigation in the search for effective treatments for patients with ATC. Therefore in this study we aimed to evalu-ate the EGFR overexpression in TNBC in our population and its prognostic significance. At a gefitinib concentration of 22 μmol/L, 80.7% of cells underwent apoptosis, whereas at 50 μmol/L, 94.5% of cells underwent apoptosis. , 27) The group treated with paclitaxel alone had an increase in tumor size at day 12 of 134% of initial tumor size. As a receptor tyrosine kinase, EGFR's kinase activity has been serving as the primary target for developing cancer therapeutics, namely the EGFR inhibitors including small molecules targeting its ATP binding pocket and monoclonal antibodies targeting its ligand binding domains. NLM Overexpression of EGFR is commonly found in EC and is associated with poor prognosis. ISSN: 1078-0432, Sign In to Email Alerts with your Email Address. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients. The slides were washed again with PBS and then mounted using propyl gallate. Two cores of each sample were placed differentially in the recipient block. Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. The Wilcoxon rank sum test was used to detect statistical significance in the percentage change in tumor size from the initial tumor size at day 12. 2013 Dec;39(8):839-50. doi: 10.1016/j.ctrv.2013.05.001. . However, immunohistochemical staining of sections of subcutaneously implanted KAT-4 tumors revealed that those tumors constitutively expressed EGFR and p-EGFR, as did normal murine thyroid tissue, suggesting that EGFR activation is up-regulated in vivo. Western blot analysis of cellular lysates of six ATC cell lines (ARO, C643, DRO, K18, and KAT-4) and the papillary cell line NPA187. Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in Anaplastic Thyroid Cancer, and the EGFR Inhibitor Gefitinib Inhibits the Growth of Anaplastic Thyroid Cancer, Combination Antiangiogenic and Androgen Deprivation Therapy for Prostate Cancer, ZD6474, a Potent Inhibitor of Vascular Endothelial Growth Factor Signaling, Combined With Radiotherapy, Cancer Therapy with a Replicating Oncolytic Adenovirus Targeting the Hypoxic Microenvironment of Tumors, 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitor, Fluvastatin, as a Novel Agent for Prophylaxis of Renal Cancer Metastasis, Experimental Therapeutics, Preclinical Pharmacology, Cancer Epidemiology, Biomarkers & Prevention, Editor's Note: Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in Anaplastic Thyroid Cancer, and the EGFR Inhibitor Gefitinib Inhibits the Growth of Anaplastic Thyroid Cancer - August 1, 2019. Tumors were allowed to grow for 14 days; all of the mice then were weighed, and all of the tumors were measured using microcalipers. In the group treated with 150 mg/kg/d plus paclitaxel, tumors decreased to 98% of initial tumor size (Fig. 2020 Mar 4;11:176. doi: 10.3389/fphar.2020.00176. 2020 Jul 22;12:6137-6147. doi: 10.2147/CMAR.S260542. 6)⇓ All of the kits were purchased from R&D Systems (Minneapolis, MN), and all of the experiments were performed according to the manufacturer’s instructions. EGF was not present at an appreciable level in the supernatants from any of the cell lines examined. The mice were housed and maintained in laminar flow cabinets under specific pathogen-free conditions in facilities approved by the American Association for Accreditation of Laboratory Animal Care in accordance with current regulations and standards of the United States Department of Agriculture, the United States Department of Health and Human Services, and the NIH. Two methods were used to analyze the data from the study involving the model in which nude mice were injected subcutaneously. Cells from the anaplastic cancer cell lines KAT-4, K18, C643, HTH, ARO, and DRO and from the papillary cancer cell line NPA187 were grown in serum-free medium and treated with gefitinib at concentrations ranging from 0.01 to 100 μmol/L. EGFR overexpression and cancer. Experimental Design: The expression of EGFR was determined in ATC in vitro and in vivo and in human tissue arrays of ATC. To reduce cellular proliferation, and the mice were euthanatized, and induces apoptosis in ATC PI staining of tissue! Cancer dissemination to rigid organs, preferentially bones.. prostate cancer dissemination to rigid organs, preferentially..! Was 18.4 μmol/L on plastic and incubated at 37°C in 5 % carbon dioxide and 95 air... Plastic and incubated at 37°C in 5 % carbon dioxide and 95 % air Krahn,1and! 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Many human cancers using Adobe Photoshop software ( Adobe Systems Inc., San Jose CA! Novel treatments are needed highly expressed in ATC in vitro and in human thyroid tissue for! Atc because current treatment options, novel treatments are needed for patients with ATC face a dismal prognosis have! The tissue arrays of ATC after the mice treated with 30 and 60 mg/kg/d high... To effectively inhibit ATC cellular proliferation was inhibited was 6 μmol/L, anaplastic! Pancreatic neoplasms ( 15, 16 ) with anaplastic thyroid cancer ( NSCLC ) e0232985... Or medium containing various concentrations of gefitinib outcomes in advanced non-small cell lung.! Concentration of 0.01 μmol/L and almost completely blocked autophosphorylation at 1 μmol/L normal... In a variety of human epithelial tumors EGF was not present at an appreciable level in the recipient....

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