EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines
Autor(a) principal: | |
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Data de Publicação: | 2009 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/67585 |
Resumo: | Purpose: The epidermal growth factor receptor (EGFR) is amplified and overexpressed in adult glioblastoma, with response to targeted inhibition dependent on the underlying biology of the disease. EGFR has thus far been considered to play a less important role in pediatric glioma, although extensive data are lacking. We have sought to clarify the role of EGFR in pediatric high-grade glioma (HGG). Experimental Design: We retrospectively studied a total of 90 archival pediatric HGG specimens for EGFR protein overexpression, gene amplification, and mutation and assessed the in vitro sensitivity of pediatric glioma cell line models to the small-molecule EGFR inhibitor erlotinib. Results: Amplification was detected in 11% of cases, with corresponding overexpression of the receptor. No kinase or extracellular domain mutations were observed; however, 6 of 35 (17%) cases harbored the EGFRvIII deletion, including two anaplastic oligodendrogliomas and a gliosarcoma overexpressing EGFRvIII in the absence of gene amplification and coexpressing platelet-derived growth factor receptor α. Pediatric glioblastoma cells transduced with wild-type or deletion mutant EGFRvIII were not rendered more sensitive to erlotinib despite expressing wild-type PTEN. Phosphorylated receptor tyrosine kinase profiling showed a specific activation of platelet-derived growth factor receptor α/β in EGFRvIII-transduced pediatric glioblastoma cells, and targeted coinhibition with erlotinib and imatinib leads to enhanced efficacy in this model. Conclusions: These data identify an elevated frequency of EGFR gene amplification and EGFRvIII mutation in pediatric HGG than previously recognized and show the likely necessity of targeting multiple genetic alterations in the tumors of these children. |
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EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell linesAdolescentBlotting, WesternCell ProliferationChildErbB ReceptorsErlotinib HydrochlorideGliomaHumansPrognosisQuinazolinesRetrospective StudiesReverse Transcriptase Polymerase Chain ReactionSensitivity and SpecificityTumor Cells, CulturedSequence DeletionScience & TechnologyPurpose: The epidermal growth factor receptor (EGFR) is amplified and overexpressed in adult glioblastoma, with response to targeted inhibition dependent on the underlying biology of the disease. EGFR has thus far been considered to play a less important role in pediatric glioma, although extensive data are lacking. We have sought to clarify the role of EGFR in pediatric high-grade glioma (HGG). Experimental Design: We retrospectively studied a total of 90 archival pediatric HGG specimens for EGFR protein overexpression, gene amplification, and mutation and assessed the in vitro sensitivity of pediatric glioma cell line models to the small-molecule EGFR inhibitor erlotinib. Results: Amplification was detected in 11% of cases, with corresponding overexpression of the receptor. No kinase or extracellular domain mutations were observed; however, 6 of 35 (17%) cases harbored the EGFRvIII deletion, including two anaplastic oligodendrogliomas and a gliosarcoma overexpressing EGFRvIII in the absence of gene amplification and coexpressing platelet-derived growth factor receptor α. Pediatric glioblastoma cells transduced with wild-type or deletion mutant EGFRvIII were not rendered more sensitive to erlotinib despite expressing wild-type PTEN. Phosphorylated receptor tyrosine kinase profiling showed a specific activation of platelet-derived growth factor receptor α/β in EGFRvIII-transduced pediatric glioblastoma cells, and targeted coinhibition with erlotinib and imatinib leads to enhanced efficacy in this model. Conclusions: These data identify an elevated frequency of EGFR gene amplification and EGFRvIII mutation in pediatric HGG than previously recognized and show the likely necessity of targeting multiple genetic alterations in the tumors of these children.Cancer Research UK grants C1178/A10294, C309/A2187, and C309/A8274; Oak Foundation (L. Marshall); La Fondation de France (N. Gaspar); and Breakthrough Breast Cancer (J.S. Reis-Filho). We acknowledge NHS funding to the National Institute for Health Research Biomedical Research Centre.American Association for Cancer Research[et al.]Universidade do MinhoBax, Dorine A.Gaspar, NathalieLittle, Suzanne E.Marshall, LynleyPerryman, LaraRegairaz, MariePereira, Marta Sofia Carvalho Ribeiro VianaVuononvirta, RaisaSharp, Swee Y.Reis, R. M.2009-09-152009-09-15T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/67585eng1078-04321557-326510.1158/1078-0432.CCR-08-321019737945info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:20:11Zoai:repositorium.sdum.uminho.pt:1822/67585Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:13:16.221731Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines |
title |
EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines |
spellingShingle |
EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines Bax, Dorine A. Adolescent Blotting, Western Cell Proliferation Child ErbB Receptors Erlotinib Hydrochloride Glioma Humans Prognosis Quinazolines Retrospective Studies Reverse Transcriptase Polymerase Chain Reaction Sensitivity and Specificity Tumor Cells, Cultured Sequence Deletion Science & Technology |
title_short |
EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines |
title_full |
EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines |
title_fullStr |
EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines |
title_full_unstemmed |
EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines |
title_sort |
EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines |
author |
Bax, Dorine A. |
author_facet |
Bax, Dorine A. Gaspar, Nathalie Little, Suzanne E. Marshall, Lynley Perryman, Lara Regairaz, Marie Pereira, Marta Sofia Carvalho Ribeiro Viana Vuononvirta, Raisa Sharp, Swee Y. Reis, R. M. |
author_role |
author |
author2 |
Gaspar, Nathalie Little, Suzanne E. Marshall, Lynley Perryman, Lara Regairaz, Marie Pereira, Marta Sofia Carvalho Ribeiro Viana Vuononvirta, Raisa Sharp, Swee Y. Reis, R. M. |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
[et al.] Universidade do Minho |
dc.contributor.author.fl_str_mv |
Bax, Dorine A. Gaspar, Nathalie Little, Suzanne E. Marshall, Lynley Perryman, Lara Regairaz, Marie Pereira, Marta Sofia Carvalho Ribeiro Viana Vuononvirta, Raisa Sharp, Swee Y. Reis, R. M. |
dc.subject.por.fl_str_mv |
Adolescent Blotting, Western Cell Proliferation Child ErbB Receptors Erlotinib Hydrochloride Glioma Humans Prognosis Quinazolines Retrospective Studies Reverse Transcriptase Polymerase Chain Reaction Sensitivity and Specificity Tumor Cells, Cultured Sequence Deletion Science & Technology |
topic |
Adolescent Blotting, Western Cell Proliferation Child ErbB Receptors Erlotinib Hydrochloride Glioma Humans Prognosis Quinazolines Retrospective Studies Reverse Transcriptase Polymerase Chain Reaction Sensitivity and Specificity Tumor Cells, Cultured Sequence Deletion Science & Technology |
description |
Purpose: The epidermal growth factor receptor (EGFR) is amplified and overexpressed in adult glioblastoma, with response to targeted inhibition dependent on the underlying biology of the disease. EGFR has thus far been considered to play a less important role in pediatric glioma, although extensive data are lacking. We have sought to clarify the role of EGFR in pediatric high-grade glioma (HGG). Experimental Design: We retrospectively studied a total of 90 archival pediatric HGG specimens for EGFR protein overexpression, gene amplification, and mutation and assessed the in vitro sensitivity of pediatric glioma cell line models to the small-molecule EGFR inhibitor erlotinib. Results: Amplification was detected in 11% of cases, with corresponding overexpression of the receptor. No kinase or extracellular domain mutations were observed; however, 6 of 35 (17%) cases harbored the EGFRvIII deletion, including two anaplastic oligodendrogliomas and a gliosarcoma overexpressing EGFRvIII in the absence of gene amplification and coexpressing platelet-derived growth factor receptor α. Pediatric glioblastoma cells transduced with wild-type or deletion mutant EGFRvIII were not rendered more sensitive to erlotinib despite expressing wild-type PTEN. Phosphorylated receptor tyrosine kinase profiling showed a specific activation of platelet-derived growth factor receptor α/β in EGFRvIII-transduced pediatric glioblastoma cells, and targeted coinhibition with erlotinib and imatinib leads to enhanced efficacy in this model. Conclusions: These data identify an elevated frequency of EGFR gene amplification and EGFRvIII mutation in pediatric HGG than previously recognized and show the likely necessity of targeting multiple genetic alterations in the tumors of these children. |
publishDate |
2009 |
dc.date.none.fl_str_mv |
2009-09-15 2009-09-15T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/67585 |
url |
http://hdl.handle.net/1822/67585 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1078-0432 1557-3265 10.1158/1078-0432.CCR-08-3210 19737945 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
American Association for Cancer Research |
publisher.none.fl_str_mv |
American Association for Cancer Research |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799132570598768640 |