TMOD-09. EGFRvIII INCREASES MISMATCH REPAIR PROTEIN EXPRESSION AND IS THEREFORE A PREDICTIVE MARKER FOR TEMOZOLOMIDE RESPONSE IN O6-METHYLGUANINE-DNA METHYLTRANSFERASE NEGATIVE GLIOBLASTOMA CELLS AND TUMORS

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with an extremely poor prognosis. The standard therapy involves surgery followed by irradiation and temozolomide (TMZ) treatment. Epigenetic silencing of the O6-methylguanine-DNA-methyltransferase (MGMT) gene is the only predictive biomarker that is associated with TMZ response. Hence the establishment of new markers, which predict treatment response is therefore of significant interest. Approximately 20-30% of GBMs display expression of the epidermal growth factor receptor (EGFR) variant III (EGFRvIII), which is constitutively activated. The aim of the present study was to analyse the impact of endogenous EGFRvIII expression on TMZ sensitivity of cell cultures and tumor xenografts. Using isogenic pairs of MGMT methylated GBM cells we observed that EGFRvIII expression was associated with a significant increase in TMZ sensitivity in vitro and in vivo. Knockdown of EGFRvIII restored TMZ resistance, confirming EGFRvIII dependent TMZ sensitivity. TMZ sensitivity in MGMT negative cells is predominantly determined by functional mismatch repair (MMR). In agreement with this, we found that EGFRvIII expression was associated with an upregulated MMR protein expression in cells and in tumor xenografts. Remarkably even a slight decrease in MSH6 and MLH1 expression restored TMZ resistance. Moreover EGFRvIII expressing cells showed more DNA damage after TMZ treatment. In accordance with our findings statistica...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MODELS Source Type: research