Special Issue "EGFR Family Signaling in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2016)

Special Issue Editor

Guest Editor
Prof. Zhixiang Wang

Signal Transduction Research Group, Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
Website | E-Mail
Phone: +1-780-492-0710
Fax: +1-780-492-1998
Interests: ErbB receptors; cell signaling; protein trafficking; breast cancer; small GTPases and cell cycle

Special Issue Information

Dear Colleagues,

The epidermal growth factor receptor (EGFR) family (also known as ERBB family) of transmembrane receptor tyrosine kinases consists of four members including EGFR (ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). EGFR family receptors were quickly linked to human cancer following their identification more than three decades ago. Mutation and overexpression of EGFR family have been closely associated with many types of cancers, including breast cancer, lung cancer, head and neck cancer, ovarian cancer, colorectal cancer, gastric cancer, glioma, melanoma, and medulloblastoma. EGFR family-mediated signal transduction in normal and cancer cells have been intensively studied and the vast signaling network downstream of EGFR family receptors have been largely revealed. EGFR family receptors have also been frequently targeted for cancer therapy and several agents targeting EGFR family receptors have been approved by the FDA and significantly improved treatment of the related cancers. However, novel signaling pathways and cell functions are continuously identified as regulated by EGFR family receptors. Due to the limitation and resistance of the currently available cancer therapies, EGFR family receptors are still intensively explored for developing novel therapies targeting various cancers. This Special Issue will cover the recent progress in all of the areas related to EGFR family signaling and cancer.

Prof. Dr. Zhixiang Wang
Guest Edito

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


Published Papers (5 papers)

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Review

Open AccessReview Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways
Received: 7 April 2017 / Revised: 10 May 2017 / Accepted: 10 May 2017 / Published: 17 May 2017
Cited by 81 | PDF Full-text (2311 KB) | HTML Full-text | XML Full-text
Abstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR [...] Read more.
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation. These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression. We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways. We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors. Full article
(This article belongs to the Special Issue EGFR Family Signaling in Cancer)
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Open AccessReview HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance
Received: 21 February 2017 / Revised: 10 April 2017 / Accepted: 21 April 2017 / Published: 26 April 2017
Cited by 10 | PDF Full-text (1497 KB) | HTML Full-text | XML Full-text
Abstract
HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% [...] Read more.
HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab. Full article
(This article belongs to the Special Issue EGFR Family Signaling in Cancer)
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Open AccessReview ErbB Family Signalling: A Paradigm for Oncogene Addiction and Personalized Oncology
Received: 23 February 2017 / Revised: 5 April 2017 / Accepted: 6 April 2017 / Published: 12 April 2017
Cited by 8 | PDF Full-text (954 KB) | HTML Full-text | XML Full-text
Abstract
ErbB family members represent important biomarkers and drug targets for modern precision therapy. They have gained considerable importance as paradigms for oncoprotein addiction and personalized medicine. This review summarizes the current understanding of ErbB proteins in cell signalling and cancer and describes the [...] Read more.
ErbB family members represent important biomarkers and drug targets for modern precision therapy. They have gained considerable importance as paradigms for oncoprotein addiction and personalized medicine. This review summarizes the current understanding of ErbB proteins in cell signalling and cancer and describes the molecular rationale of prominent cases of ErbB oncoprotein addiction in different cancer types. In addition, we have highlighted experimental technologies for the development of innovative cancer cell models that accurately predicted clinical ErbB drug efficacies. In the future, such cancer models might facilitate the identification and validation of physiologically relevant novel forms of oncoprotein and non-oncoprotein addiction or synthetic lethality. The identification of genotype-drug response relationships will further advance personalized oncology and improve drug efficacy in the clinic. Finally, we review the most important drugs targeting ErbB family members that are under investigation in clinical trials or that made their way already into clinical routine. Taken together, the functional characterization of ErbB oncoproteins have significantly increased our knowledge on predictive biomarkers, oncoprotein addiction and patient stratification and treatment. Full article
(This article belongs to the Special Issue EGFR Family Signaling in Cancer)
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Open AccessReview EGFR Family Members’ Regulation of Autophagy Is at a Crossroads of Cell Survival and Death in Cancer
Received: 4 March 2017 / Revised: 15 March 2017 / Accepted: 21 March 2017 / Published: 24 March 2017
Cited by 16 | PDF Full-text (846 KB) | HTML Full-text | XML Full-text
Abstract
The epidermal growth factor receptor (EGFR) signaling pathways are altered in many cancers contributing to increased cell survival. These alterations are caused mainly through increased expression or mutation of EGFR family members EGFR, ErbB2, ErbB3, and ErbB4. These receptors have been successfully targeted [...] Read more.
The epidermal growth factor receptor (EGFR) signaling pathways are altered in many cancers contributing to increased cell survival. These alterations are caused mainly through increased expression or mutation of EGFR family members EGFR, ErbB2, ErbB3, and ErbB4. These receptors have been successfully targeted for cancer therapy. Specifically, a monoclonal antibody against ErbB2, trastuzumab, and a tyrosine kinase inhibitor against EGFR, gefitinib, have improved the survival of breast and lung cancer patients. Unfortunately, cancer patients frequently become resistant to these inhibitors. This has led to investigating how EGFR can contribute to cell survival and how cancer cells can overcome inhibition of its signaling. Indeed, it is coming into focus that EGFR signaling goes beyond a single signal triggering cell proliferation and survival and is a sensor that regulates the cell’s response to microenvironmental stresses such as hypoxia. It acts as a switch that modulates the ability of cancer cells to survive. Autophagy is a process of self-digestion that is inhibited by EGFR allowing cancer cells to survive under stresses that would normally cause death and become resistant to chemotherapy. Inhibiting EGFR signaling allows autophagy to contribute to cell death. This gives new opportunities to develop novel therapeutic strategies to treat cancers that rely on EGFR signaling networks and autophagy. In this review, we summarize the current understanding of EGFR family member regulation of autophagy in cancer cells and how new therapeutic strategies could be developed to overcome drug resistance. Full article
(This article belongs to the Special Issue EGFR Family Signaling in Cancer)
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Open AccessReview Epidermal Growth Factor Pathway Signaling in Drosophila Embryogenesis: Tools for Understanding Cancer
Received: 14 December 2016 / Revised: 2 February 2017 / Accepted: 3 February 2017 / Published: 7 February 2017
Cited by 8 | PDF Full-text (917 KB) | HTML Full-text | XML Full-text
Abstract
EGF signaling is a well-known oncogenic pathway in animals. It is also a key developmental pathway regulating terminal and dorsal-ventral patterning along with many other aspects of embryogenesis. In this review, we focus on the diverse roles for the EGF pathway in Drosophila [...] Read more.
EGF signaling is a well-known oncogenic pathway in animals. It is also a key developmental pathway regulating terminal and dorsal-ventral patterning along with many other aspects of embryogenesis. In this review, we focus on the diverse roles for the EGF pathway in Drosophila embryogenesis. We review the existing body of evidence concerning EGF signaling in Drosophila embryogenesis focusing on current uncertainties in the field and areas for future study. This review provides a foundation for utilizing the Drosophila model system for research into EGF effects on cancer. Full article
(This article belongs to the Special Issue EGFR Family Signaling in Cancer)
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