EGFR-Driven Phenotypes Dictate Differential Therapeutic Response to Radiotherapy and Temozolomide in Glioblastoma

Abstract Despite the established Stupp regimen, glioblastoma (GBM) remains a highly lethal cancer with a 5-year survival rate below 10%. The epidermal growth factor receptor (EGFR) is frequently amplified or mutated in GBM, and we have previously shown that different EGFR statuses correlate with distinct tumor phenotypes and responses to temozolomide (TMZ). In this study, we investigated the differential response of two mouse GBM models, one overexpressing EGFRwt (EGFRwt/amp) and the other with overexpressing the EGFRvIII variant, to radiotherapy (RT) alone and in combination with TMZ. While both tumor models were sensitive to RT in vitro, in vivo experiments showed no significant survival benefit from RT for mice carrying EGFRwt/amp GBM, regardless of the RT schedule. Moreover, for these tumors, different combinations of RT with TMZ were not significantly better than spaced TMZ treatment alone. In contrast, EGFRvIII tumors responded well to RT alone, and spacing out the RT doses offered no additional benefit. Although a Stupp-like protocol provided a small benefit compared to RT alone in this model, the combinatorial treatment also induced the expression of several resistance markers, such as MGMT or NF-κb phosphorylation. Our retrospective analysis of patient data supports these findings, suggesting that RT alone may not improve survival for patients with EGFRwt/amp GBM, whereas for GBM with EGFRvIII mutations, adding RT or TMZ and RT, does provide a clear survival benefit to surgery or to surgery and RT, respectively. These results suggest that EGFR status could serve as a crucial biomarker to predict tumor response and guide personalized treatment decisions, particularly in cases where minimizing toxicity is a priority. Competing Interest Statement The authors have declared no competing interest.