مورد إلكتروني
Most clinical anti-EGFR antibodies do not neutralize both wtEGFR and EGFRvIII activation in glioma.
| العنوان: | Most clinical anti-EGFR antibodies do not neutralize both wtEGFR and EGFRvIII activation in glioma. |
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| بيانات النشر: | Oxford University Press United Kingdom 2020-05-13 |
| تفاصيل مُضافة: | McKenzie M. Kuchibhotla M. Chen S.C. McDonald K.L. Kornblum H.I. Endersby R. Adams T.E. Johns T.G. Bentley J. Greenall S.A. Pearce L. Dolezal O. Seminova E. |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Background: Although epidermal growth factor receptor (EGFR) and its truncated, autoactive mutant EGFR variant (v)III are bona fide drivers of tumorigenesis in some gliomas, therapeutic antibodies developed to neutralize this axis have not improved patient survival in a limited number of trials. Previous studies using cells transduced to exogenously express EGFRvIII may have compromised mechanistic studies of anti-EGFR therapeutics. Therefore, we re-assessed the activity of clinical EGFR antibodies in patient-derived gliomaspheres that endogenously express EGFRvIII. Method(s): The antitumor efficacy of antibodies was assessed using in vitro proliferation assays and intracranial orthografts. Receptor activation status, antibody engagement, oncogenic signaling, and mechanism of action after antibody treatment were analyzed by immunoprecipitation and western blotting. Tracking of antibody receptor complexes was conducted using immunofluorescence. Result(s): The EGFR domain III-targeting antibodies cetuximab, necitumumab, nimotuzumab, and matuzumab did not neutralize EGFRvIII activation. Chimeric monoclonal antibody 806 (ch806) neutralized EGFRvIII, but not wild-type (wt)EGFR activation. Panitumumab was the only antibody that neutralized both EGFRvIII and wtEGFR, leading to reduction of p-S6 signaling and superior in vitro and in vivo antitumor activity. Mechanistically, panitumumab induced recycling of receptor but not degradation as previously described. Panitumumab, via its unique avidity, stably cross-linked EGFRvIII to prevent its activation, while ch806 induced a marked reduction in the active EGFRvIII disulphide-bonded dimer. Conclusion(s): We discovered a previously unknown major resistance mechanism in glioma in that most EGFR domain III-targeting antibodies do not neutralize EGFRvIII. The superior in vitro and in vivo antitumor activity of panitumumab supports further clinical testing of this antibody against EGFRvIII-stratified glioma.Copyright © 2019 The Aut |
| مصطلحات الفهرس: | protein cleavage, protein cross linking, protein degradation, protein expression, protein phosphorylation, signal transduction, upregulation, antineoplastic monoclonal antibody/cb [Drug Combination], antineoplastic monoclonal antibody/dt [Drug Therapy], antineoplastic monoclonal antibody/ip [Intraperitoneal Drug Administration], antineoplastic monoclonal antibody/pd [Pharmacology], cetuximab/cb [Drug Combination], cetuximab/dt [Drug Therapy], cetuximab/pd [Pharmacology], epidermal growth factor receptor/ec [Endogenous Compound], epidermal growth factor receptor antibody/ec [Endogenous Compound], immunoglobulin Fc fragment/ec [Endogenous Compound], matuzumab/dt [Drug Therapy], matuzumab/pd [Pharmacology], mitogen activated protein kinase 3/ec [Endogenous Compound], necitumumab/dt [Drug Therapy], necitumumab/pd [Pharmacology], nimotuzumab/dt [Drug Therapy], nimotuzumab/pd [Pharmacology], panitumumab/dt [Drug Therapy], panitumumab/pd [Pharmacology], protein S6/ec [Endogenous Compound], unclassified drug, ch 806/cb [Drug Combination], ch 806/dt [Drug Therapy], ch 806/ip [Intraperitoneal Drug Administration], ch 806/pd [Pharmacology], amino terminal sequence, animal experiment, animal model, antineoplastic activity, antiproliferative activity, article, cancer survival, carboxy terminal sequence, carcinogenesis, cell proliferation, controlled study, disulfide bond, drug efficacy, drug targeting, enzyme phosphorylation, glioblastoma/dt [Drug Therapy], glioblastoma/et [Etiology], glioblastoma cell line, human, human cell, in vitro study, in vivo study, internalization, mouse, nonhuman, Article |
| URL: | Neuro-Oncology Click here for full text options LibKey Link |
| الإتاحة: | Open access content. Open access content Copyright 2020 Elsevier B.V., All rights reserved. |
| أرقام أخرى: | AUSHL oai:repository.monashhealth.org:1/35355 Neuro-Oncology. 21 (8) (pp 1016-1027), 2019. Date of Publication: 01 Aug 2019. 1522-8517 https://repository.monashhealth.org/monashhealthjspui/handle/1/35355 31002307 [http://www.ncbi.nlm.nih.gov/pubmed/?term=31002307] 631537521 (Greenall) Department of Oncology, Monash University and Monash Health, Clayton, VIC, Australia (Greenall, Chen) Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia (Greenall, McDonald, Endersby, Johns) Brain Cancer Discovery Collaborative, NSW, Australia (McKenzie) School of Life and Environmental Sciences, Deakin University, Geelong, VIC, Australia (McKenzie) Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia (McKenzie, Chen) Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia (Seminova, Dolezal, Pearce, Bentley, Adams) CSIRO Manufacturing, Parkville, VIC, Australia (Kuchibhotla, Endersby, Johns) Cancer Centre, Telethon Kids Institute, Nedlands, WA, Australia (McDonald) Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales, NSW, Australia (Kornblum) Intellectual and Developmental Disabilities Research Center, University of California, Los Angeles, CA, United States Greenall S.A.; sameer.greenall@monash.edu 1305128383 |
| المصدر المساهم: | MONASH HEALTH LIBRS From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1305128383 |
| قاعدة البيانات: | OAIster |
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