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EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma

The oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). T...

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Autores principales: Struve, Nina, Binder, Zev A., Stead, Lucy F., Brend, Tim, Bagley, Stephen J., Faulkner, Claire, Ott, Leonie, Müller-Goebel, Justus, Weik, Anna-Sophie, Hoffer, Konstantin, Krug, Leonie, Rieckmann, Thorsten, Bußmann, Lara, Henze, Marvin, Morrissette, Jennifer J. D., Kurian, Kathreena M., Schüller, Ulrich, Petersen, Cordula, Rothkamm, Kai, O´ Rourke, Donald M., Short, Susan C., Kriegs, Malte
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142016/
https://www.ncbi.nlm.nih.gov/pubmed/32066879
http://dx.doi.org/10.1038/s41388-020-1208-5
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author Struve, Nina
Binder, Zev A.
Stead, Lucy F.
Brend, Tim
Bagley, Stephen J.
Faulkner, Claire
Ott, Leonie
Müller-Goebel, Justus
Weik, Anna-Sophie
Hoffer, Konstantin
Krug, Leonie
Rieckmann, Thorsten
Bußmann, Lara
Henze, Marvin
Morrissette, Jennifer J. D.
Kurian, Kathreena M.
Schüller, Ulrich
Petersen, Cordula
Rothkamm, Kai
O´ Rourke, Donald M.
Short, Susan C.
Kriegs, Malte
author_facet Struve, Nina
Binder, Zev A.
Stead, Lucy F.
Brend, Tim
Bagley, Stephen J.
Faulkner, Claire
Ott, Leonie
Müller-Goebel, Justus
Weik, Anna-Sophie
Hoffer, Konstantin
Krug, Leonie
Rieckmann, Thorsten
Bußmann, Lara
Henze, Marvin
Morrissette, Jennifer J. D.
Kurian, Kathreena M.
Schüller, Ulrich
Petersen, Cordula
Rothkamm, Kai
O´ Rourke, Donald M.
Short, Susan C.
Kriegs, Malte
author_sort Struve, Nina
collection PubMed
description The oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). Therefore, we retrospectively analyzed the survival of 336 GBM patients, demonstrating that under standard treatment, which includes TMZ, EGFRvIII expression is associated with prolonged survival, but only in patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated tumors. Using isogenic GBM cell lines with endogenous EGFRvIII expression we could demonstrate that EGFRvIII increases TMZ sensitivity and results in enhanced numbers of DNA double-strand breaks and a pronounced S/G2-phase arrest after TMZ treatment. We observed a higher expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cells and patient tumor samples, which was most pronounced for MSH2 and MSH6. EGFRvIII-specific knockdown reduced MMR protein expression thereby increasing TMZ resistance. Subsequent functional kinome profiling revealed an increased activation of p38- and ERK1/2-dependent signaling in EGFRvIII expressing cells, which regulates MMR protein expression downstream of EGFRvIII. In summary, our results demonstrate that the oncoprotein EGFRvIII sensitizes a fraction of GBM to current standard of care treatment through the upregulation of DNA MMR.
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spelling pubmed-71420162020-04-13 EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma Struve, Nina Binder, Zev A. Stead, Lucy F. Brend, Tim Bagley, Stephen J. Faulkner, Claire Ott, Leonie Müller-Goebel, Justus Weik, Anna-Sophie Hoffer, Konstantin Krug, Leonie Rieckmann, Thorsten Bußmann, Lara Henze, Marvin Morrissette, Jennifer J. D. Kurian, Kathreena M. Schüller, Ulrich Petersen, Cordula Rothkamm, Kai O´ Rourke, Donald M. Short, Susan C. Kriegs, Malte Oncogene Article The oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). Therefore, we retrospectively analyzed the survival of 336 GBM patients, demonstrating that under standard treatment, which includes TMZ, EGFRvIII expression is associated with prolonged survival, but only in patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated tumors. Using isogenic GBM cell lines with endogenous EGFRvIII expression we could demonstrate that EGFRvIII increases TMZ sensitivity and results in enhanced numbers of DNA double-strand breaks and a pronounced S/G2-phase arrest after TMZ treatment. We observed a higher expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cells and patient tumor samples, which was most pronounced for MSH2 and MSH6. EGFRvIII-specific knockdown reduced MMR protein expression thereby increasing TMZ resistance. Subsequent functional kinome profiling revealed an increased activation of p38- and ERK1/2-dependent signaling in EGFRvIII expressing cells, which regulates MMR protein expression downstream of EGFRvIII. In summary, our results demonstrate that the oncoprotein EGFRvIII sensitizes a fraction of GBM to current standard of care treatment through the upregulation of DNA MMR. Nature Publishing Group UK 2020-02-17 2020 /pmc/articles/PMC7142016/ /pubmed/32066879 http://dx.doi.org/10.1038/s41388-020-1208-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Struve, Nina
Binder, Zev A.
Stead, Lucy F.
Brend, Tim
Bagley, Stephen J.
Faulkner, Claire
Ott, Leonie
Müller-Goebel, Justus
Weik, Anna-Sophie
Hoffer, Konstantin
Krug, Leonie
Rieckmann, Thorsten
Bußmann, Lara
Henze, Marvin
Morrissette, Jennifer J. D.
Kurian, Kathreena M.
Schüller, Ulrich
Petersen, Cordula
Rothkamm, Kai
O´ Rourke, Donald M.
Short, Susan C.
Kriegs, Malte
EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma
title EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma
title_full EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma
title_fullStr EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma
title_full_unstemmed EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma
title_short EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma
title_sort egfrviii upregulates dna mismatch repair resulting in increased temozolomide sensitivity of mgmt promoter methylated glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142016/
https://www.ncbi.nlm.nih.gov/pubmed/32066879
http://dx.doi.org/10.1038/s41388-020-1208-5
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