Activation of Epidermal Growth Factor Receptor Sensitizes Glioblastoma Cells to Hypoxia-Induced Cell Death

Abstract

Background: The epidermal growth factor receptor (EGFR) signaling pathway is genetically activated in approximately 50% of glioblastomas (GBs). Its inhibition has been explored clinically but produced disappointing results, potentially due to metabolic effects that protect GB cells against nutrient deprivation and hypoxia. Here, we hypothesized that EGFR activation could disable metabolic adaptation and define a GB cell population sensitive to starvation. Methods: Using genetically engineered GB cells to model different types of EGFR activation, we analyzed changes in metabolism and cell survival under conditions of the tumor microenvironment. Results: We found that expression of mutant EGFRvIII as well as EGF stimulation of EGFR-overexpressing cells impaired physiological adaptation to starvation and rendered cells sensitive to hypoxia-induced cell death. This was preceded by adenosine triphosphate (ATP) depletion and an increase in glycolysis. Furthermore, EGFRvIII mutant cells had higher levels of mitochondrial superoxides potentially due to decreased metabolic flux into the serine synthesis pathway which was associated with a decrease in the NADPH/NADP+ ratio. Conclusions: The finding that EGFR activation renders GB cells susceptible to starvation could help to identify a subgroup of patients more likely to benefit from starvation-inducing therapies.

Double Recombinant Vaccinia Virus: A Candidate Drug against Human Glioblastoma

“…It can be assumed that cancer cells cultured with the addition of epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and nutritional supplements acquire certain properties, due to which the treatment with VV-GMCSF-Lact is more effective. Amplification of the epidermal growth factor receptor (EGFR) gene is known to be observed in more than 50% of glioblastoma cases [22]. The addition of EGF in the medium is able to stimulate the EGFR-dependent signaling pathways, such as phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) [23,24].…”

Efficacy of osimertinib plus bevacizumab in glioblastoma patients with simultaneous EGFR amplification and EGFRvIII mutation

“…Furthermore, osimertinib inhibits the constitutive activity of EGFRvIII with high potency (< 100 nM) in a tyrosine kinase-dependent manner (31). In addition, it has been recently found that cells expressing mutant EGFRvIII are prone to starvation and hypoxia-induced cell death (32). This research supports the idea that using anti-VEGF agents that produce a low-oxygen environment could promote EGFRvIII-mutant hypoxiainduced cell death.…”

“…There is increasing experimental and clinical evidence that activation of EGFR and downstream signaling pathways render speci c subgroups of GBs vulnerable to hypoxia-inducing therapies. Hypoxia-induced cell death in GB models is preceded by ATP depletion, increase in glycolysis and higher levels of mitochondrial superoxides which have been associated with decreased metabolic ux and decreased NADPH/NADP + ratio (53). The di culty in effectively tackling tumor cells lies on the ample heterogeneity amongst various GB samples and models.…”

Impact of Neoadjuvant Bevacizumab on Neuroradiographic Response and Histological Findings Related to Tumor Stemness and the Hypoxic Tumor Microenvironment in Glioblastoma: Paired Comparison Between Newly Diagnosed and Recurrent Glioblastomas

“…According to a previous report (47), mutant epidermal growth factor receptor variant III (EGFR vIII) mutation and EGFR overexpression glioma cells impaired physiological adaptation to starvation and rendered cells sensitive to hypoxia-induced cell death. Theoretically, the activation of EGFR enhances vulnerability to hypoxia-inducing therapies via a decrease in Nicotinamide adenine dinucleotide phosphate (NAPDH) levels.…”