An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma

Abstract

Despite all of the progress in understanding its molecular biology and pathogenesis, glioblastoma (GBM) is one of the most aggressive types of cancers, and without an efficient treatment modality at the moment, it remains largely incurable. Nowadays, one of the most frequently studied molecules with important implications in the pathogenesis of the classical subtype of GBM is the epidermal growth factor receptor (EGFR). Although many clinical trials aiming to study EGFR targeted therapies have been performed, none of them have reported promising clinical results when used in glioma patients. The resistance of GBM to these therapies was proven to be both acquired and innate, and it seems to be influenced by a cumulus of factors such as ineffective blood–brain barrier penetration, mutations, heterogeneity and compensatory signaling pathways. Recently, it was shown that EGFR possesses kinase-independent (KID) pro-survival functions in cancer cells. It seems imperative to understand how the EGFR signaling pathways function and how they interconnect with other pathways. Furthermore, it is important to identify the mechanisms of drug resistance and to develop better tailored therapeutic agents.

Multi‐omics analysis reveals the association between specific solute carrier proteins gene expression patterns and the immune suppressive microenvironment in glioma

“…In glioblastoma, high CD99 expression has been found to promote tumour cell migration, invasion and the formation of an immune‐suppressive microenvironment 51,52 . Overactive activation of the EGF signalling pathway is a crucial feature in glioblastoma, playing a pivotal role in the progression of the disease 53 . Neoangiogenesis is a significant feature of tumours, and the excessive activation of the VEGF signalling pathway plays a crucial role in this process 54 .…”

Design, Synthesis, and Biological Evaluation of Newly Synthesized Cinnamide-Fluorinated Containing Compounds as Bioactive Anticancer Agents

“…Epidermal growth factor receptor (EGFR) was the first receptor to be sequenced and discovered to possess tyrosine kinase activity . EGFR has been shown to be aberrantly expressed or activated in a number of tumors. , The downstream signaling effects of such aberration lead to impaired apoptosis, enhanced proliferation, angiogenesis, and metastatic spread. , Therefore, the inhibition of the EGFR signaling pathway has become a valuable approach in the treatment of cancer . One effective approach to inhibit EGFR-mediated signaling is to compete with ATP for binding to the tyrosine domain of EGFR utilizing small molecules of tyrosine kinase inhibitors (TKIs) .…”

Chromosome 7 to the rescue: overcoming chromosome 10 loss in gliomas

“…The evidence relating the roles and relationships of EGFR and chromosome 7 gains is complex, however. EGFR is one of the most studied among the > 50 human receptor tyrosine kinases, but the mysteries of EGFR are still being elucidated 53 . EGFR amplifications often co-occurs with aberrant transcripts, especially a transcript denoted EGFRvIII, which lead to constitutive EGFR signaling 11 .…”

“…EGFR amplifications often co-occurs with aberrant transcripts, especially a transcript denoted EGFRvIII, which lead to constitutive EGFR signaling 11 . EGFR has both kinase-dependent and kinase-independent pro-tumorigenic functions 53 . EGFR aberrations in GBM may manifest in at least six ways that are not mutually exclusive: i) activating point mutations, ii) genomic amplification, iii) chromosomal rearrangements, iv) autocrine signaling, especially between mutant forms of EGFR, such as EGFRvIII, v) intragenic duplication of the kinase domain, vi) EGFR fusions with pieces of other genes 53 .…”

“…EGFR has both kinase-dependent and kinase-independent pro-tumorigenic functions 53 . EGFR aberrations in GBM may manifest in at least six ways that are not mutually exclusive: i) activating point mutations, ii) genomic amplification, iii) chromosomal rearrangements, iv) autocrine signaling, especially between mutant forms of EGFR, such as EGFRvIII, v) intragenic duplication of the kinase domain, vi) EGFR fusions with pieces of other genes 53 . High-level EGFR amplifications may occur either on double minute chromosomes or via insertions of extra copies of EGFR on otherwise normal chromosome 7 54 .…”