Updated Insights on EGFR Signaling Pathways in Glioma

Abstract

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood-brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

Keywords: EGFR; clinical trials; glioma; pathways.

Figure 1

EGFR signaling pathway (EGFR—epithelial growth factor receptor, EGFRvIII—Epidermal growth factor receptor variant III, Pi3K—Phosphoinositide 3-kinase, RAS—family of genes involving cellular signal transduction, PTEN—Phosphatase and tensin homolog, NF1—Neurofibromatosis type 1, RAF—serine/threonine-specific protein kinases, MEK—Mitogen-activated protein kinase, ERK—extracellular signal-regulated kinase, AkT—Protein kinase B, mTOR—mammalian target of rapamycin, Src—Proto-oncogene tyrosine-protein kinase, cMyc—c proto-oncogene, NFKB—nuclear factor kappa-light-chain-enhancer of activated B cells, Block arrow—inhibition activity, Point arrow—pathway flow).

Figure 2

EGFR-based therapies in glioblastoma. (BBB—blood brain barrier, mABs—monoclonal antibodies, CAR-T—Chimeric anti-gen receptor T cell therapy)