1. EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma.
- Author
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Struve N, Binder ZA, Stead LF, Brend T, Bagley SJ, Faulkner C, Ott L, Müller-Goebel J, Weik AS, Hoffer K, Krug L, Rieckmann T, Bußmann L, Henze M, Morrissette JJD, Kurian KM, Schüller U, Petersen C, Rothkamm K, O Rourke DM, Short SC, and Kriegs M
- Subjects
- Animals, Brain Neoplasms genetics, Brain Neoplasms mortality, Cell Line, Tumor, Chemoradiotherapy methods, Cohort Studies, DNA Methylation, DNA Mismatch Repair drug effects, DNA Mismatch Repair genetics, DNA Modification Methylases metabolism, DNA Repair Enzymes metabolism, DNA-Binding Proteins genetics, ErbB Receptors genetics, ErbB Receptors metabolism, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Glioblastoma genetics, Glioblastoma mortality, Humans, Kaplan-Meier Estimate, MAP Kinase Signaling System genetics, Mice, MutS Homolog 2 Protein genetics, Mutation, Promoter Regions, Genetic genetics, Retrospective Studies, Temozolomide therapeutic use, Tumor Suppressor Proteins metabolism, Up-Regulation, Xenograft Model Antitumor Assays, Brain Neoplasms therapy, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Drug Resistance, Neoplasm genetics, Glioblastoma therapy, Temozolomide pharmacology, Tumor Suppressor Proteins genetics
- Abstract
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.
- Published
- 2020
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