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

  1. Struve, Nina
  2. Binder, Zev A.
  3. Stead, Lucy ORCID logo
  4. Brend, Tim
  5. Bagley, Stephen J.
  6. Faulkner, Claire
  7. Ott, Leonie
  8. Müller-Goebel, Justus
  9. Weik, Anna-Sophie
  10. Hoffer, Konstantin
  11. Krug, Leonie
  12. Rieckmann, Thorsten
  13. Bußmann, Lara ORCID logo
  14. Henze, Marvin
  15. Morrissette, Jennifer J. D.
  16. Kurian, Kathreena M.
  17. Schüller, Ulrich ORCID logo
  18. Petersen, Cordula
  19. Rothkamm, Kai
  20. O ́ Rourke, Donald M.
  21. Short, Susan C.
  22. Kriegs, Malte

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1000 Titel
  • EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma
1000 Autor/in
  1. Struve, Nina |
  2. Binder, Zev A. |
  3. Stead, Lucy |
  4. Brend, Tim |
  5. Bagley, Stephen J. |
  6. Faulkner, Claire |
  7. Ott, Leonie |
  8. Müller-Goebel, Justus |
  9. Weik, Anna-Sophie |
  10. Hoffer, Konstantin |
  11. Krug, Leonie |
  12. Rieckmann, Thorsten |
  13. Bußmann, Lara |
  14. Henze, Marvin |
  15. Morrissette, Jennifer J. D. |
  16. Kurian, Kathreena M. |
  17. Schüller, Ulrich |
  18. Petersen, Cordula |
  19. Rothkamm, Kai |
  20. O ́ Rourke, Donald M. |
  21. Short, Susan C. |
  22. Kriegs, Malte |
1000 Erscheinungsjahr 2020
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2020-02-17
1000 Erschienen in
1000 Quellenangabe
  • 39(15):3041-3055
1000 Copyrightjahr
  • 2020
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1038/s41388-020-1208-5 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142016/ |
1000 Publikationsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
lokal Gene Expression Regulation, Neoplastic [MeSH]
lokal Cell Line, Tumor [MeSH]
lokal Tumor Suppressor Proteins/genetics [MeSH]
lokal DNA Modification Methylases/metabolism [MeSH]
lokal Up-Regulation [MeSH]
lokal DNA-Binding Proteins/genetics [MeSH]
lokal Cohort Studies [MeSH]
lokal ErbB Receptors/metabolism [MeSH]
lokal Tumor Suppressor Proteins/metabolism [MeSH]
lokal DNA Repair Enzymes/metabolism [MeSH]
lokal Cell signalling
lokal Xenograft Model Antitumor Assays [MeSH]
lokal Drug Resistance, Neoplasm/genetics [MeSH]
lokal MutS Homolog 2 Protein/genetics [MeSH]
lokal Brain Neoplasms/mortality [MeSH]
lokal Glioblastoma/genetics [MeSH]
lokal Temozolomide/pharmacology [MeSH]
lokal Female [MeSH]
lokal Mutation [MeSH]
lokal Brain Neoplasms/genetics [MeSH]
lokal Kaplan-Meier Estimate [MeSH]
lokal Humans [MeSH]
lokal Gene Knockdown Techniques [MeSH]
lokal Chemoradiotherapy/methods [MeSH]
lokal DNA Repair Enzymes/genetics [MeSH]
lokal CNS cancer
lokal ErbB Receptors/genetics [MeSH]
lokal Retrospective Studies [MeSH]
lokal DNA Mismatch Repair/drug effects [MeSH]
lokal Animals [MeSH]
lokal DNA Mismatch Repair/genetics [MeSH]
lokal Glioblastoma/therapy [MeSH]
lokal DNA Modification Methylases/genetics [MeSH]
lokal Promoter Regions, Genetic/genetics [MeSH]
lokal Mice [MeSH]
lokal Article
lokal Glioblastoma/mortality [MeSH]
lokal MAP Kinase Signaling System/genetics [MeSH]
lokal DNA Methylation [MeSH]
lokal DNA mismatch repair
lokal Temozolomide/therapeutic use [MeSH]
lokal Brain Neoplasms/therapy [MeSH]
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/uri/U3RydXZlLCBOaW5h|https://frl.publisso.de/adhoc/uri/QmluZGVyLCBaZXYgQS4=|https://orcid.org/0000-0002-9550-4150|https://frl.publisso.de/adhoc/uri/QnJlbmQsIFRpbQ==|https://frl.publisso.de/adhoc/uri/QmFnbGV5LCBTdGVwaGVuIEou|https://frl.publisso.de/adhoc/uri/RmF1bGtuZXIsIENsYWlyZQ==|https://frl.publisso.de/adhoc/uri/T3R0LCBMZW9uaWU=|https://frl.publisso.de/adhoc/uri/TcO8bGxlci1Hb2ViZWwsIEp1c3R1cw==|https://frl.publisso.de/adhoc/uri/V2VpaywgQW5uYS1Tb3BoaWU=|https://frl.publisso.de/adhoc/uri/SG9mZmVyLCBLb25zdGFudGlu|https://frl.publisso.de/adhoc/uri/S3J1ZywgTGVvbmll|https://frl.publisso.de/adhoc/uri/UmllY2ttYW5uLCBUaG9yc3Rlbg==|https://orcid.org/0000-0001-6302-0859|https://frl.publisso.de/adhoc/uri/SGVuemUsIE1hcnZpbg==|https://frl.publisso.de/adhoc/uri/TW9ycmlzc2V0dGUsIEplbm5pZmVyIEouIEQu|https://frl.publisso.de/adhoc/uri/S3VyaWFuLCBLYXRocmVlbmEgTS4=|https://orcid.org/0000-0002-8731-1121|https://frl.publisso.de/adhoc/uri/UGV0ZXJzZW4sIENvcmR1bGE=|https://frl.publisso.de/adhoc/uri/Um90aGthbW0sIEthaQ==|https://frl.publisso.de/adhoc/uri/T8K0IFJvdXJrZSwgRG9uYWxkIE0u|https://frl.publisso.de/adhoc/uri/U2hvcnQsIFN1c2FuIEMu|https://frl.publisso.de/adhoc/uri/S3JpZWdzLCBNYWx0ZQ==
1000 Hinweis
  • DeepGreen-ID: 86b03ed7620040f2b822fd266d22c88c ; metadata provieded by: DeepGreen (https://www.oa-deepgreen.de/api/v1/), LIVIVO search scope life sciences (http://z3950.zbmed.de:6210/livivo), Crossref Unified Resource API (https://api.crossref.org/swagger-ui/index.html), to.science.api (https://frl.publisso.de/), ZDB JSON-API (beta) (https://zeitschriftendatenbank.de/api/), lobid - Dateninfrastruktur für Bibliotheken (https://lobid.org/resources/search)
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1000 Erstellt am 2023-11-18T12:40:12.500+0100
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1000 Zuletzt bearbeitet Fri Dec 01 14:10:36 CET 2023
1000 Objekt bearb. Fri Dec 01 14:10:36 CET 2023
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