egf receptor kinase domain mutations in lung cancer

Key “driver” mutations have been discovered in specific subgroups of non-small-cell lung cancer (NSCLC) patients. Clinical use of TKIs is effective in a subset of lung cancers with mutations in the EGFR kinase domain, rendering the receptor highly susceptible to TKIs. Responses were most pronounced in female non‐smokers with adenocarcinoma histology. CA2961437A1 CA2961437A CA2961437A CA2961437A1 CA 2961437 A1 CA2961437 A1 CA 2961437A1 CA 2961437 A CA2961437 A CA 2961437A CA 2961437 A CA2961437 A CA 2961437A CA 2961437 A1 CA2961437 A1 CA 2961437A1 Authority CA Canada Prior art keywords del ins … Corresponding Author. Although mutations can occur anywhere within the TK domain, a significant set of EGFR mutations in lung cancer that are associated with objective response to single agent TKI therapy are observed in exons 18–21. Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) will experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. To understand the role of human epidermal growth factor receptor (hEGFR) kinase domain mutations in lung tumorigenesis and response to EGFR-targeted therapies, we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in human lung cancer. EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. To study the role of ligand expression in mediating response to EGFR antagonism, we injected NCI-H441 [EGFR and EGF/transforming growth factor-α (TGF-α) positive] or PC14-PE6 (EGFR positive and EGF/TGF-α … Main text. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer. Mutations in the epidermal growth factor receptor (EGFR) kinase domain occur in 10–30% of lung adenocarcinoma and are associated with tyrosine kinase inhibitor (TKI) sensitivity. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). In lung cancer, the molecules gefitinib and erlotinib which target the intracellular kinase domain of the epidermal growth factor receptor (EGFR), cause significant tumour responses and, in the case of erlotinib, a survival benefit in patients with previously treated cancers. Mutations in the kinase domain of epidermal growth factor receptor (EGFR) occur in around 10% of patients with lung adenocarcinoma in the western world and 25–30% of patients in Asian countries [2–4]. About 40% of genetic alterations found in highly-responsive CrossRef PubMed Google Scholar. Clinical use of TKIs is effective in a subset of lung cancers with mutations in the EGFR kinase domain, rendering the receptor highly susceptible to TKIs. Le récepteur de l'EGF (Epidermal Growth Factor) ou EGFR est une protéine monomérique transmembranaire qui transduit le signal consécutif à sa liaison au facteur de croissance épidermique.C'est une protéine à activité tyrosine kinase intrinsèque. Il présente des similitudes avec le récepteur de l'insuline.Il appartient à la RTK famille des récepteurs à activité tyrosine kinase. 1–3 However, the overwhelming majority of these patients inevitably develop acquired … INTRODUCTION. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. 47. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Sei Hoon Yang , Leah E. Mechanic , Ping Yang , Maria Teresa Landi , Elise D. Bowman , Jason Wampfler , Daoud Meerzaman , Kyeong Man Hong , Felicia Mann , Tatiana Dracheva , Junya Fukuoka , William Travis , Neil E. Caporaso , Curtis C. Harris and Jin Jen However, these benefits are limited, and emergence of additional EGFR mutations usually results in TKI resistance and disease progression. Please share how this access benefits you. Your story matters Citation Jorge, S.E.D.C., S.S. Kobayashi, and D.B. 239000005483 tyrosine kinase inhibitors Substances 0.000 claims description 26 229940121647 EGFR inhibitors Drugs 0.000 claims description 24 MUTATIONS IN THE EPIDERMAL GROWTH FACTOR RECEPTOR KINASE DOMAIN However, these benefits are limited, and emergence of additional EGFR mutations usually results in TKI resistance and disease progression. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor‐sensitizing and resistance mutations in the plasma DNA of patients with advanced non–small cell lung cancer during treatment with erlotinib . We sought to identify the immediate direct and indirect phosphorylation targets of mutant EGFRs in lung adenocarcinoma. Exons 18–21 of the tyrosine kinase domain of EGFR harbor all key mutations. Pao W, Miller V, Zakowski M et al. Costa. Previously, we showed one mechanism linking cigarette smoke to EGFR-driven lung cancer. Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) were identified in approximately 15% of all patients with non-small cell lung cancer (NSCLC). EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004;101:13306–13311. The most frequent of these are in-frame deletions in exon 19 that occur in approximately 45% of cases, followed by point mutations in exon 21, in 40–45% of cases. Clinical use of TKIs is effective in a subset of lung cancers with mutations in the EGFR kinase domain, rendering the receptor highly susceptible to TKIs. These mutations endow the receptor with constitutive kinase activity. Mutations in the epidermal growth factor receptor kinase domain Download PDF Info Publication number CA2961437A1. Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark. Lung adenocarcinoma is the most common histology associated with lung cancer patients. In ERBB3, 3 mutations were found in the ligand binding domain. Epidermal growth factor receptor (EGFR) has been extensively targeted in the treatment of non–small cell lung cancer, producing responses in a small number of patients. Frederick L, Wang XY, Eley G et al. Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC).Classical activating mutations (exon 19 deletions and the L858R point mutation) comprise the vast majority of EGFR mutations and are well defined as strong predictors for good clinical response to EGFR tyrosine kinase inhibitors (EGFRi). Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. EGF receptor mutations in lung cancer: From humans to mice and maybe back to humans Deletions in exon 19 and nucleotide substitutions in exon 21 are the most common mutations of the EGFR (ErbB1) in NSCLC. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib William Pao, Vincent Miller, Maureen Zakowski, Jennifer Doherty, Katerina Politi, Inderpal Sarkaria, Bhuvanesh Singh, Robert Heelan, Valerie Rusch, Lucinda Fulton , Elaine Mardis, Doris Kupfer, Richard Wilson, Mark Kris, Harold Varmus the cytoplasmic domain of EGFR in lung adenocar-cinomas, while, in contrast, mutations in glioblastomas showing constitutive EGFR signaling target theextracel-lular domain of this receptor [14,15]. 2014. Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data The Harvard community has made this article openly available. Proc Natl Acad Sci USA 2004;101:13306–13311. Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. In 2004, three groups reported somatic mutations in the EGFR gene in non-small cell lung cancer (NSCLC) (Lynch et al., 2004, Paez et al., 2004, Pao et al., 2004).The mutations are either short, in-frame deletions or insertions or substitutions clustered around the region encoding the ATP binding pocket of the receptor's tyrosine kinase domain in exons 18–21. Hyo Sup Shim, Da Hye Lee, Eun Ju Park, Se Hoon Kim, Histopathologic Characteristics of Lung Adenocarcinomas With Epidermal Growth Factor Receptor Mutations in the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Lung Adenocarcinoma Classification, Archives of Pathology & Laboratory Medicine, 10.5858/arpa.2010 … Boe S. Sorensen MS, PhD. Previously, we showed one mechanism linking cigarette smoke to EGFR-driven lung cancer. Pao W, Miller V, Zakowski M, et al. One of those mutations found in EPHA3 kinase domain, K761N, is located at a highly conserved position analogous to the mutation K641 in FGFR2. Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinaseinhibitor.In-framedeletionsoccurinexon19,whereaspoint mutations occur frequently in … Receptor tyrosine kinases (RTKs) are activated by somatic genetic alterations in a subset of cancers, and such cancers are often sensitive to specific inhibitors of the activated kinase. Background Most patients with non–small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). Proc Natl Acad Sci U … EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitiv- ity of tumors to gefitinib and erlotinib. The EGFR receptor tyrosine kinase is frequently mutated in lung cancer, but the mechanism by which mutations activate kinase activity are not clear. Non–Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation AmitK.Das,1 MitsuoSato,2 MichaelD.Story,1 MichaelPeyton,2 RobertGraves,7 StellaRedpath,7 LucGirard,2 AdiF.Gazdar,2 JerryW.Shay,3 JohnD.Minna,2,4,5,6 andChaitanyaS.Nirodi1 Activating mutations in the form of deletions in exon 19 (del 19) or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict outcome to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Two well-established examples of this paradigm include lung cancers with either EGFR mutations or ALK translocations. 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