Targeting EGFR in Glioblastoma: Molecular Biology and Current Understanding

Abstract

Glioblastoma (GBM) is a heterogeneous disease comprising a multitude of genetically and epigenetically different cancers, all of them highly resistant to conventional chemo and radiotherapy. Greater characterization of GBM at the molecular level has improved its initial pathophysiological staging and classification. With this knowledge came the hope that more efficacious therapies to combat this highly lethal disease were on the horizon. One possibility for intervention was represented by the targeting of epidermal growth factor receptor (EGFR), which is amplified and/or mutated in more than 50% of patients. However, several tirosin-kinase inhibitors and EGFR-directed antibodies have been tested in clinical trials and only modest results have been obtained. Here, we provide an overview of the structure and expression of EGFR and its mutant forms in GBM, describing the canonical and non-canonical downstream pathways activated by the receptor. Furthermore, we enumerate some of the most relevant therapeutic strategies that have been tested so far to inhibit EGFR, discussing the possible explanations for their failure as well as novel alternative approaches.