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Epidermal Growth Factor Receptors Family: Current Insights in Neoplastic Medicine

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 June 2019) | Viewed by 17804

Special Issue Editors

Dipartimento di Patologia Umana Dell’adulto e Dell’età Evolutiva Gaetano Barresi, Divisione di Anatomia Patologica, Università Degli Studi di Messina, 98125 Messina, Italy
Interests: innate immunity; gastritis; Helicobacter pylori; neutrophils; mast cell; eosinophils
Special Issues, Collections and Topics in MDPI journals
Department of Human Pathology "Gaetano Barresi", Section of Anatomic Pathology, University of Messina, Messina 98123, Italy
Interests: Epidermal Growth Factor Receptor (EGFR); HER2 (Human Epidermal Growth Factor Receptor 2); metastases; prognosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The epidermal growth factor RTK family consists of four members: EGFR (ErbB1, HER1), ErbB2 (HER2, neu in rodents), ErbB3 (HER3) and ErbB4 (HER4). These structurally related receptors are single chain transmembrane glycoproteins consisting of an extracellular ligand-binding ectodomain, a transmembrane domain, a short juxtamembrane section, a tyrosine kinase domain and a tyrosine-containing C-terminal tail. Binding of soluble ligand to the ectodomain of the receptor promotes homo- and heterodimer formation between receptors. Receptor dimerization is essential for activation of the intracellular tyrosine kinase domain and phosphorylation of the C-terminal tail. Phosphotyrosine residues then activate, either directly or through adaptor proteins, downstream components of signaling pathways including Ras/MAPK, PLCγ1/PKC, PI(3)kinase/Akt, and STAT pathways. Through such effects on cell-cycle progression, apoptosis, angiogenesis, and tumor-cell motility, EGFR is implicated in the development and progression of cancer. Overexpression of wild-type ErbB receptors is very common in a wide range of tumors and represents a common strategy of malignancies to activate pathways downstream of ErbB receptors, thereby promoting cell proliferation, survival, invasion and metastasis.

The ErbB2 gene is frequently amplified and the protein overexpressed in several human epithelial malignancies, including breast, gastric, ovarian, and colon-rectal cancers. About 40% of primary glioblastoma multiforme (GBM) and 5–10% of NSCLCs have gene amplification of EGFR. In such tumors, the gene amplification/overexpression has been linked to a poor overall outcome and a poorly differentiated phenotype. It has also been considered a useful indicator of response to specifically targeted therapies, such as trastuzumab, which inhibit the extracellular domain of HER2. Many studies have been addressed to determine the ErbB2-positive rate, mainly in breast and gastric carcinomas, utilizing a well codified scoring system, and HER2 status assessment is currently being used in such cancers to determine patient eligibility for treatment with trastuzumab.

Our purpose is to better understand the underlying molecular mechanisms of  ErbB2 in human neoplastic disease, not only to optimize treatment outcomes but also to improve effective management modalities in malignancies. Therefore, original research articles, review articles, as well as research letters covering the large field of ErbB2 application in human cancer are strongly invited.

Prof. Dr. Giovanni Tuccari
Prof. Dr. Pio Zeppa
Dr. Antonio Ieni
Guest Editors

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Keywords

  • Epidermal Growth Factor Receptor (EGFR)
  • HER2 (Human Epidermal Growth Factor Receptor 2)
  • Metastases
  • Prognosis

Published Papers (2 papers)

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Review

20 pages, 282 KiB  
Review
Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario
by Alessandro Russo, Tindara Franchina, Giuseppina Ricciardi, Alessandra Battaglia, Maria Picciotto and Vincenzo Adamo
Int. J. Mol. Sci. 2019, 20(6), 1431; https://doi.org/10.3390/ijms20061431 - 21 Mar 2019
Cited by 75 | Viewed by 6996
Abstract
Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients. The incidence of uncommon EGFR mutations is growing, due to the wider adoption of [...] Read more.
Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients. The incidence of uncommon EGFR mutations is growing, due to the wider adoption of next-generation sequencing (NGS) for diagnostic purposes, which enables the identification of rare variants, usually missed with available commercial kits that only detect a limited number of EGFR mutations. However, the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation), since most of the pivotal studies with EGFR TKIs in the first line, with few exceptions, excluded patients with rare and/or complex variants. Recently, the third generation EGFR TKI osimertinib further revolutionized the therapeutic algorithm of EGFR-mutated NSCLC, but its role in patients harboring EGFR mutations besides exon 19 deletions and/or L858R is largely unknown. Therefore, a better knowledge of the sensitivity of uncommon mutations to currently available EGFR TKIs is critical to guiding treatment decisions in clinical practice. The aim of this paper is to provide a comprehensive overview of the treatment of NSCLC patients harboring uncommon EGFR mutations with currently approved therapies and to discuss the emerging therapeutic opportunities in this peculiar subgroup of patients, including chemo-immunotherapy combinations, next-generation EGFR TKIs, and novel targeted agents. Full article
8 pages, 365 KiB  
Review
First- and Second-Generation EGFR-TKIs Are All Replaced to Osimertinib in Chemo-Naive EGFR Mutation-Positive Non-Small Cell Lung Cancer?
by Masayuki Takeda and Kazuhiko Nakagawa
Int. J. Mol. Sci. 2019, 20(1), 146; https://doi.org/10.3390/ijms20010146 - 03 Jan 2019
Cited by 110 | Viewed by 10407
Abstract
Activating mutations of the epidermal growth factor receptor gene (EGFR) are a driving force for some lung adenocarcinomas. Several randomized phase III studies have revealed that treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) results in an improved progression-free [...] Read more.
Activating mutations of the epidermal growth factor receptor gene (EGFR) are a driving force for some lung adenocarcinomas. Several randomized phase III studies have revealed that treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) results in an improved progression-free survival (PFS) compared to standard chemotherapy in chemonaive patients with advanced non–small cell lung cancer (NSCLC), selected based on the presence of EGFR mutations. Patients treated with second-generation EGFR-TKIs have also shown an improved PFS relative to those treated with first-generation EGRF-TKIs. Osimertinib is a third-generation EGFR-TKI that still irreversibly inhibits the activity of EGFR after it has acquired the secondary T790M mutation that confers resistance to first- and second-generation drugs. Its efficacy has been validated for patients whose tumors have developed T790M-mediated resistance, as well as for first-line treatment of those patients with EGFR mutation–positive NSCLC. Although there are five EGFR-TKIs (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) currently available for the treatment of EGFR-mutated lung cancer, the optimal sequence for administration of these drugs remains to be determined. In this review, we addressed this issue with regard to maximizing the duration of the EGFR-TKI treatment. Full article
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