Inhibition of Brain Epidermal Growth Factor Receptor Activation: A Novel Target in Neurodegenerative Diseases and Brain Injuries

Abstract

Several reports have been published recently demonstrating a beneficial effect of epidermal growth factor receptor (EGFR) inhibitors in improving pathologic and behavioral conditions in neurodegenerative diseases (NDDs) such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS) as well as the brain and spinal cord injuries (SCI). Despite successful therapeutic effects of EGFR inhibition in these pathologic conditions, there is still no report of proof-of-concept studies in well-characterized animal models using recently developed blood-brain barrier (BBB)-penetrating EGFR inhibitors, which is due to previous conflicting reports concerning the level of EGFR or activated EGFR in normal and pathologic conditions that caused target engagement to be a concern in any future EGFR inhibition therapy. In this review, the level of EGFR expression and activation in the developing central nervous system (CNS) compared with the adult CNS will be explained as well as how neuronal injury or pathologic conditions, especially inflammation and amyloid fibrils, induce reactive astrocytes leading to an increase in the expression and activation of EGFR and, finally, neurodegeneration. Furthermore, in this review, we will discuss two main molecular mechanisms that can be proposed as the neuroprotective effects of EGFR inhibition in these pathologic conditions. We will also review the recent advances in the development of BBB-penetrating EGFR inhibitors in cancer therapy, which may eventually be repositioned for NDDs and SCI therapy in the future. SIGNIFICANCE STATEMENTBased on the lessons from the applications of EGFR inhibitors in oncology, it is concluded that EGFR inhibitors can be beneficial in treatment of neurodegenerative diseases and spinal cord injuries. They carry their therapeutic potentials through induction of autophagy and attenuation of reactive astrocytes.O.T. is supported by a grant from the W. Garfield Weston Foundation (Weston Brain Institute) [RR171033].

Ubiquilin proteins regulate EGFR levels and activity in lung adenocarcinoma cells

“…37 Thus, inhibition of RTKs could not only benefit certain cancers, but it could also be beneficial in several neurodegenerative diseases. 26,35,36 These studies further support our belief that UBQLNs regulate many processes involved in multiple diseases.…”

“…Many of these therapeutics are now being used as first-line treatment for both lung cancer and Alzheimer's patients. [24][25][26] In this study, we present data establishing the interaction of UBQLN1 and UBQLN2 with EGFR. In lung adenocarcinoma cell lines, downregulation of UBQLN1, followed by epidermal growth factor (EGF) stimulation, leads to degradation of total EGFR protein, and an increase in migration and invasion potential of these cells.…”

“…Epidermal growth factor receptor (EGFR), a transmembrane protein that is also a member of the RTK family, is mutated or overexpressed in multiple cancers and AD. [24][25][26] EGFR is one of the most commonly studied oncogenes to date. It is often upregulated in multiple cancers and downregulated in AD.…”

Microarray Analysis Identifies Key Differentially Expressed Circular RNAs in Aged Mice With Postoperative Cognitive Dysfunction

“…Egfr has also been proposed as a fundamental disease-associated protein in AD pathogenesis (Quan et al, 2020;Yuen et al, 2020). They have therapeutic abilities through autophagy induction and the attenuation of reactive astrocytes (Tavassoly et al, 2020). Prkacb might be involved in the MAPK signaling pathway, GABAergic synapse, insulin secretion, insulin signaling pathway, and chemokine signaling pathway.…”

Effect of the glycine-rich domain in GAREM2 on its unique subcellular localization upon EGF stimulation

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BackgroundIn the brain, intracellular signaling pathways mediated by cell growth factors and their receptors are important for neuronal growth and survival, and neurotransmission [1,2]. In addition to brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), EGF-and insulin-signaling pathways are also implicated in brain function [3,4], and abnormalities in these signaling systems are known to be involved in neurodegenerative diseases, such as Alzheimer's and Huntington's [5][6][7].

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