Development of novel combined therapies with anti-EGFR monoclonal antibody and anticancer drug for malignant gliomas

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Treatment of glioblastoma (GBM) cells overexpressing driver oncogenic wild-type EGFR or a mutant EGFRvIII with a humanized anti-EGFR monoclonal antibody nimotuzumab (Nimo) resulted in reduction in tyrosine phosphorylation of EGFRvIIIpreferentially, which was associated with a decrease in Akt phosphorylation. Combination treatment of nimotuzumab with temozolomide (TMZ), the standard chemotherapeutic drug for GBM, significantly suppressed growth and elongated survival of mice bearing subcutaneous or intracerebral human GBM tumors overexpressing EGFRvIII. The sensitivity to the combination treatment was affected in regrown tumor cells which had lost expression of mismatch repair (MMR) proteins MSH6 and MLH1, suggesting that the resistance to this combination treatment might involve expression changes of MMR effectors.