Targeting EGFR for treatment of glioblastoma: molecular basis to overcome resistance

Abstract

Glioblastoma (glioblastoma multiforme; GBM; WHO Grade IV) accounts for the majority of primary malignant brain tumors in adults. Amplification and mutation of the epidermal growth factor receptor (EGFR) gene represent signature genetic abnormalities encountered in GBM. A range of potential therapies that target EGFR or its mutant constitutively active form, ΔEGFR, including tyrosine kinase inhibitors (TKIs), monoclonal antibodies, vaccines, and RNA-based agents, are currently in development or in clinical trials for the treatment of GBM. Data from experimental studies evaluating these therapies have been very promising; however, their efficacy in the clinic has so far been limited by both upfront and acquired drug resistance. This review discusses the current status of anti-EGFR agents and the recurrent problem of resistance to these agents that strongly indicates that a multiple target approach will provide a more favorable future for these types of targeted therapies in GBM.

Figure 1

Malignant glioma and therapeutic resistance. GBMs are adept at evading inhibition of EGFR receptor function through several possible mechanisms. (1) Brain tumor cells that are intractable to DNA damage-induced apoptosis may also tolerate apoptotic cues driven by TKI-mediated inhibition of EGFR. Combinatorial therapy using inhibitors of anti-apoptotic activity may overcome this cross-resistance. (2) Intratumoral diversity within GBM tumors may drive resistance to single based anti-EGFR agents due to: RTK co-activation, PTEN deletion/mutations, and tumor cell-tumor cell interactions via secreted molecules. PTEN* denotes mutation (3) Efflux of EGFR TKIs and increased genetic stability may lead to the maintenance of CSC populations and tumor relapse. (4) Enhanced immunosuppression mediated by circulating growth factors, cytokines and suppressor T cells can antagonize the systemic immune responses generated by anti-EGFR immunotherapies. Additionally, circulating IL-6 in the tumor microenvironment can facilitate resistance intracellularly via activation of the JAK/STAT3/Bcl-xL pathway.