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Epidermal growth factor receptor (EGFR) is a key molecule in the classical subtype, yet clinical trials of EGFR-targeted therapies have not produced promising results in glioma patients. Resistance is both innate and acquired, driven by factors such as limited blood–brain barrier penetration, mutations, tumor heterogeneity, and compensatory signaling. 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An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma. Int. J. Mol. Sci. 2023, 24, 11110. [https://](https://)[ ](https://)[doi.org/10.3390/ijms241311110](doi.org/10.3390/ijms241311110)  \nAcademic Editor: Doriano Fabbro  \nReceived: 4 June 2023  \nRevised: 29 June 2023  \nAccepted: 3 July 2023  \nPublished: 5 July 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Neurosurgical Department, Clinical Emergency Hospital “Bagdasar-Arseni”, Soseaua Berceni 12,  \n041915 Bucharest, Romania; [mara.silvia@icloud.com](mara.silvia@icloud.com) (S.M.B.R.); [kamel.amyra@yahoo.com](kamel.amyra@yahoo.com) (A.K.); [dr_vghciubotaru@yahoo.com](dr_vghciubotaru@yahoo.com) (G.V.C.); [ligia.tataranu@umfcd.ro](ligia.tataranu@umfcd.ro) (L.G.T.)  \n2 Neuromuscular Rehabilitation Department, Clinical Emergency Hospital “Bagdasar-Arseni”, Soseaua Berceni  \n12, 041915 Bucharest, Romania; [gelu.onose@umfcd.ro](gelu.onose@umfcd.ro)  \n3 Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2–4, 710204 Craiova, Romania; [ani.sevastre@umfcv.ro](ani.sevastre@umfcv.ro)  \n4 Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2–4, 710204 Craiova, Romania; [veronicasfredel@yahoo.com](veronicasfredel@yahoo.com) (V.S.); [suzdanoiu@gmail.com](suzdanoiu@gmail.com) (S.D.)  \n5 Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2–4, 710204 Craiova, Romania  \n6 Department of Neurosurgery, Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 020022 Bucharest, Romania  \n* Correspondence: [anica.dricu@umfcv.ro](anica.dricu@umfcv.ro)  \nAbstract: 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.  \nKeywords: glioblastoma; RTK; growth factor; EGFR; signaling pathways; EGFR targeted therapy  \n1. Introduction  \nGlioblastoma multiforme (GBM, World Health Organization [WHO] grade 4 glioma) represents the most common, aggressive, and malignant cen","cbCaibMJQ5Q0tjz1","https://ap.wps.com/l/cbCaibMJQ5Q0tjz1","pdf",2021738,24,"English","# Abstract\n# Keywords\n# 1. Introduction","[{\"question\":\"Why are EGFR-targeted therapies ineffective in glioblastoma patients?\",\"answer\":\"Clinical trials have not reported promising results in glioma patients. Resistance is both acquired and innate, influenced by multiple factors.\"},{\"question\":\"What factors contribute to GBM resistance to EGFR-targeted therapies?\",\"answer\":\"Resistance is associated with ineffective blood–brain barrier penetration, EGFR mutations, tumor heterogeneity, and compensatory signaling pathways.\"},{\"question\":\"What is the significance of kinase-independent (KID) EGFR functions?\",\"answer\":\"EGFR can exert kinase-independent pro-survival functions in cancer cells. This makes understanding EGFR signaling and its pathway interconnections essential for improving treatment strategies.\"}]","An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma | PDF",1790233836]