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.
Highlights
Glioblastoma (GBM, glioma WHO grade IV) is the most common malignant brain tumor in humans
EGFRvIII expression is associated with better response to standard of care treatment To test if EGFRvIII has an influence on TMZ sensitivity we retrospectively analyzed the overall survival of 336 patients with IDH1 wild type GBM and known methylation of the O6methylguanine-DNA methyltransferase (MGMT) promoter, epidermal growth factor receptor (EGFR) amplification and EGFRvIIII status who had been treated with standard of care
We observed a significant association with survival for MGMT promoter methylation status (Fig. 1a; hazard ratio [HR] = 0.52; 95% CI = 0.39–0.68; p < 0.0001), and age (Fig. S1; HR = 1.02; 95% CI = 1.01–1.04; p = 0.002), demonstrating shorter survival for elderly patients
Summary
Glioblastoma (GBM, glioma WHO grade IV) is the most common malignant brain tumor in humans. While it is well accepted that IDH status and MGMT promoter status have prognostic significance in predicting patient survival after standard therapy [3,4,5], the influence of EGFR amplification and EGFRvIII expression on patient survival is still under controversial debate To address this issue we performed a retrospective survival analysis of GBM patients with known IDH, MGMT and EGFR/EGFRvIII status, who had been treated with surgery, irradiation and TMZ. The EGFRvIII is caused by an in-frame deletion of EGFR exons 2–7 It is predominantly associated with an EGFR amplification and is expressed in approximately onethird of all primary GBM [6, 7]. In a previous study using isogenic GBM cells with differences in endogenous EGFRvIII expression we had demonstrated that EGFRvIII has no impact on cellular radiosensitivity [20]. Due to the recent and ongoing development and clinical assessment of various EGFR and EGFRvIII-targeting strategies, such as peptidebased vaccines (rindopepimut), monoclonal antibody immunotoxin conjugates (ABT-414) or EGFRvIII-specific chimeric antigen receptor (CAR) T cells a deeper understanding of the molecular biology and clinical relevance of EGFR amplification and EGFRvIII in GBM is definitely required [24,25,26,27]
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