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Cancers
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EGFR Signaling in Cancer
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EGFR Signaling in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 45876

Special Issue Editors

Prof. Dr. Naoto T. Ueno

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Guest Editor
Translational and Clinical Research Program, University of Hawai’i Cancer Center, Honolulu, HI 96813, USA
Interests: triple-negative breast cancer; inflammatory breast cancer; bone metastasis; metastatic breast cancer; early drug development
Special Issues, Collections and Topics in MDPI journals
Dr. Xiaoping Wang

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Guest Editor
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: Inflammatory breast cancer; targeted therapy; signaling pathway; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The epidermal growth factor receptor (EGFR) pathway plays important roles in many cellular processes, including cell growth, differentiation, motility, inflammation, and stem cell biology. The overexpression or mutation of EGFR is associated with the development of various types of cancers, such as breast cancer, lung cancer, glioblastoma, and colorectal cancer. The EGFR pathway regulates tumorigenesis and metastasis through its downstream PI3K/AKT, MEK/ERK, and JAK/STAT signaling. It also regulates the interactions between tumor cells and the surrounding tumor microenvironment. As a result, the EGFR pathway represents an attractive therapeutic target for cancer treatment. Clinical trials of EGFR-targeted therapy with monoclonal antibodies or tyrosine kinase inhibitors have shown efficacy in some cancer types. Still, EGFR-targeted therapy is not very effective in other cancer types, and some patients develop drug resistance. It is critical to elucidate the biological function of the EGFR pathway in regulating tumor cells and the tumor microenvironment as well as establish more effective combination therapies with anti-EGFR agents.

This Special Issue will highlight novel findings on different aspects of the EGFR pathway, including, but not limited to: 1) the function of EGFR signaling pathway in tumors and the tumor microenvironment in different cancer types; and 2) the mechanism of resistance to EGFR-targeted therapy and approaches to overcoming this resistance. We hope that this Special Issue will advance our understanding of the EGFR pathway in tumor progression and lead to improved treatments and prolonged survival for cancer patients.

Dr. Naoto T. Ueno
Dr. Xiaoping Wang
Guest Editor

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 submissions that pass pre-check are 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 semimonthly 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 2900 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.

Keywords

  • epidermal growth factor receptor (EGFR)
  • tumor microenvironment
  • drug resistance

Related Special Issue

Published Papers (7 papers)

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Research

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12 pages, 3010 KiB  
Article
NSAIDs Overcome PIK3CA Mutation-Mediated Resistance to EGFR Inhibition in Head and Neck Cancer Preclinical Models
by Hua Li, Noah D. Peyser, Yan Zeng, Patrick K. Ha, Daniel E. Johnson and Jennifer R. Grandis
Cancers 2022, 14(3), 506; https://doi.org/10.3390/cancers14030506 - 20 Jan 2022
Cited by 6 | Viewed by 1787
Abstract
Epidermal growth factor receptor (EGFR) inhibitors are approved by the Food and Drug Administration (FDA) but remain under active clinical investigation for the treatment of both newly diagnosed and recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Despite EGFR expression in the majority [...] Read more.
Epidermal growth factor receptor (EGFR) inhibitors are approved by the Food and Drug Administration (FDA) but remain under active clinical investigation for the treatment of both newly diagnosed and recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Despite EGFR expression in the majority of HNSCC tumors, the levels of total or phosphorylated EGFR have not consistently been correlated with a response to EGFR targeting agents. The lack of predictive biomarkers represents a major obstacle to successful use of these drugs. Activation of phosphatidylinositol 3-kinase (PI3K) signaling by mutation of the PIK3CA oncogene represents a plausible mechanism for EGFR inhibitor drug resistance. We compared the impact of EGFR inhibitors, alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs), in preclinical HNSCC models harboring mutant versus wild-type PIK3CA. Our results demonstrate additive or synergistic effects of NSAIDs and EGFR inhibitors in vitro and in vivo in PIK3CA-mutated HNSCC models. These findings suggest that the addition of NSAIDs to EGFR inhibitors for the treatment of HNSCC may represent a promising therapeutic strategy in PIK3CA-mutated cancers. Full article
(This article belongs to the Special Issue EGFR Signaling in Cancer)
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21 pages, 6897 KiB  
Article
Erb-b2 Receptor Tyrosine Kinase 2 (ERBB2) Promotes ATG12-Dependent Autophagy Contributing to Treatment Resistance of Breast Cancer Cells
by Yongqiang Chen, Ruobing Wang, Shujun Huang, Elizabeth S. Henson, Jayce Bi and Spencer B. Gibson
Cancers 2021, 13(5), 1038; https://doi.org/10.3390/cancers13051038 - 02 Mar 2021
Cited by 12 | Viewed by 3472
Abstract
The epidermal growth factor receptor (EGFR) family member erb-b2 receptor tyrosine kinase 2 (ERBB2) is overexpressed in many types of cancers leading to (radio- and chemotherapy) treatment resistance, whereas the underlying mechanisms are still unclear. Autophagy is known to contribute to [...] Read more.
The epidermal growth factor receptor (EGFR) family member erb-b2 receptor tyrosine kinase 2 (ERBB2) is overexpressed in many types of cancers leading to (radio- and chemotherapy) treatment resistance, whereas the underlying mechanisms are still unclear. Autophagy is known to contribute to cancer treatment resistance. In this study, we demonstrate that ERBB2 increases the expression of different autophagy genes including ATG12 (autophagy-related 12) and promotes ATG12-dependent autophagy. We clarify that lapatinib, a dual inhibitor for EGFR and ERBB2, promoted autophagy in cells expressing only EGFR but inhibited autophagy in cells expressing only ERBB2. Furthermore, breast cancer database analysis of 35 genes in the canonical autophagy pathway shows that the upregulation of ATG12 and MAP1LC3B is associated with a low relapse-free survival probability of patients with ERBB2-positive breast tumors following treatments. Downregulation of ERBB2 or ATG12 increased cell death induced by chemotherapy drugs in ERBB2-positive breast cancer cells, whereas upregulation of ERBB2 or ATG12 decreased the cell death in ERBB2-negative breast cancer cells. Finally, ERBB2 antibody treatment led to reduced expression of ATG12 and autophagy inhibition increasing drug or starvation-induced cell death in ERBB2-positive breast cancer cells. Taken together, this study provides a novel approach for the treatment of ERBB2-positive breast cancer by targeting ATG12-dependent autophagy. Full article
(This article belongs to the Special Issue EGFR Signaling in Cancer)
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19 pages, 2385 KiB  
Article
A Novel Bispecific Antibody Targeting EGFR and VEGFR2 Is Effective against Triple Negative Breast Cancer via Multiple Mechanisms of Action
by Nishant Mohan, Xiao Luo, Yi Shen, Zachary Olson, Atul Agrawal, Yukinori Endo, David S. Rotstein, Lorraine C. Pelosof and Wen Jin Wu
Cancers 2021, 13(5), 1027; https://doi.org/10.3390/cancers13051027 - 01 Mar 2021
Cited by 23 | Viewed by 4299
Abstract
Both EGFR and VEGFR2 frequently overexpress in TNBC and cooperate with each other in autocrine and paracrine manner to enhance tumor growth and angiogenesis. Therapeutic mAbs targeting EGFR (cetuximab) and VEGFR2 (ramucirumab) are approved by FDA for numerous cancer indications, but none of [...] Read more.
Both EGFR and VEGFR2 frequently overexpress in TNBC and cooperate with each other in autocrine and paracrine manner to enhance tumor growth and angiogenesis. Therapeutic mAbs targeting EGFR (cetuximab) and VEGFR2 (ramucirumab) are approved by FDA for numerous cancer indications, but none of them are approved to treat breast cancers. TNBC cells secrete VEGF-A, which mediates angiogenesis on endothelial cells in a paracrine fashion, as well as promotes cancer cell growth in autocrine manner. To disrupt autocrine/paracrine loop in TNBC models in addition to mediating anti-EGFR tumor growth signaling and anti-VEGFR2 angiogenic pathway, we generated a BsAb co-targeting EGFR and VEGFR2 (designated as anti-EGFR/VEGFR2 BsAb), using publicly available sequences in which cetuximab IgG backbone is connected to the single chain variable fragment (scFv) of ramucirumab via a glycine linker. Physiochemical characterization data shows that anti-EGFR/VEGFR2 BsAb binds to both EGFR and VEGFR2 in a similar binding affinity comparable to parental antibodies. Anti-EGFR/VEGFR2 BsAb demonstrates in vitro and in vivo anti-tumor activity in TNBC models. Mechanistically, anti-EGFR/VEGFR2 BsAb not only directly inhibits both EGFR and VEGFR2 in TNBC cells but also disrupts autocrine mechanism in TNBC xenograft mouse model. Furthermore, anti-EGFR/VEGFR2 BsAb inhibits ligand-induced activation of VEGFR2 and blocks paracrine pathway mediated by VEGF secreted from TNBC cells in endothelial cells. Collectively, our novel findings demonstrate that anti-EGFR/VEGFR2 BsAb inhibits tumor growth via multiple mechanisms of action and warrants further investigation as a targeted antibody therapeutic for the treatment of TNBC. Full article
(This article belongs to the Special Issue EGFR Signaling in Cancer)
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13 pages, 2665 KiB  
Article
De Novo T790M Mutation in an L858R Epidermal Growth Factor Receptor Mutant-Associated Lung Adenocarcinoma
by Takumi Fujiwara, Tetsu Kobayashi, Taro Yasuma, Corina N. D’Alessandro-Gabazza, Masaaki Toda, Hajime Fujimoto, Kentaro Fujiwara, Atsuro Takeshita, Kota Nishihama, Tomohito Okano, Valeria Fridman D’Alessandro, Yoshiyuki Takei, Osamu Hataji and Esteban C Gabazza
Cancers 2020, 12(10), 3074; https://doi.org/10.3390/cancers12103074 - 21 Oct 2020
Cited by 3 | Viewed by 2665
Abstract
Background: Lung cancer is the leading cause of mortality for cancer worldwide. A point mutation in exon 21 of the epidermal growth factor receptor resulting in the substitution of arginine for leucine at position 858 (L858R) is a frequent cause of lung adenocarcinoma. [...] Read more.
Background: Lung cancer is the leading cause of mortality for cancer worldwide. A point mutation in exon 21 of the epidermal growth factor receptor resulting in the substitution of arginine for leucine at position 858 (L858R) is a frequent cause of lung adenocarcinoma. Tyrosine kinase inhibitors are effective for treating patients with lung cancer associated with mutant epidermal growth factor receptors but most tumors become resistant shortly after treatment. The substitution of methionine for threonine at position 790 (T790M) on exon 20 is the most frequently acquired mutation leading to resistance to tyrosine kinase inhibitors. Whether the T790M mutation occurred after tyrosine kinase inhibitor therapy or it already existed before therapy is unclear. Methods: Here, we developed mice with tetracycline-inducible lung-specific expression of the full-length genomic DNA of the human epidermal growth factor receptor containing an L858R mutation or both L858R and T790M mutations and evaluated de novo T790M mutation in untreated transgenic mice carrying a single L858R EGFR mutation. Results: The L858R mutation-associated lung adenocarcinoma acquired de novo T790 mutation without previous therapy. Conclusions: The results of this study suggest that lung tumors may spontaneously acquire T790M mutations without any drug-related selective pressure. Full article
(This article belongs to the Special Issue EGFR Signaling in Cancer)
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Review

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16 pages, 872 KiB  
Review
Current Aspects and Future Considerations of EGFR Inhibition in Locally Advanced and Recurrent Metastatic Squamous Cell Carcinoma of the Head and Neck
by Bhamini Patel and Nabil F. Saba
Cancers 2021, 13(14), 3545; https://doi.org/10.3390/cancers13143545 - 15 Jul 2021
Cited by 10 | Viewed by 2879
Abstract
Recurrent metastatic (RM) and locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) are devasting disease states with limited therapeutic options and poor overall survival. Targeting the epidermal growth factor receptor (EGFR) is one area that has helped improve outcomes [...] Read more.
Recurrent metastatic (RM) and locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) are devasting disease states with limited therapeutic options and poor overall survival. Targeting the epidermal growth factor receptor (EGFR) is one area that has helped improve outcomes in this disease. Anti-EGFR based therapies have been shown to improve overall survival and mitigate the significant toxicities incurred from standard radiation, chemotherapy, and/or surgical options. Cetuximab, the most well-studied anti-EGFR monoclonal antibody, has demonstrated a positive impact on outcomes for RM and LA SCCHN. However, the development of early resistance to cetuximab highlights the need for a wider arsenal of therapy for RM and LA diseases. The use of immune checkpoint inhibitors has recently transformed the treatment of recurrent SCCHN. Drugs such as pembrolizumab and nivolumab have demonstrated success in recent clinical trials and have been approved for the treatment of advanced disease. Given the positive results of both EGFR targeted agents and immune checkpoint inhibitors, ongoing trials are studying their synergistic effects. Full article
(This article belongs to the Special Issue EGFR Signaling in Cancer)
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21 pages, 1602 KiB  
Review
EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance
by Mary Luz Uribe, Ilaria Marrocco and Yosef Yarden
Cancers 2021, 13(11), 2748; https://doi.org/10.3390/cancers13112748 - 01 Jun 2021
Cited by 152 | Viewed by 21756
Abstract
The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and [...] Read more.
The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms. Full article
(This article belongs to the Special Issue EGFR Signaling in Cancer)
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23 pages, 1772 KiB  
Review
EphA2 and EGFR: Friends in Life, Partners in Crime. Can EphA2 Be a Predictive Biomarker of Response to Anti-EGFR Agents?
by Mario Cioce and Vito Michele Fazio
Cancers 2021, 13(4), 700; https://doi.org/10.3390/cancers13040700 - 09 Feb 2021
Cited by 15 | Viewed by 7795
Abstract
The Eph receptors represent the largest group among Receptor Tyrosine kinase (RTK) families. The Eph/ephrin signaling axis plays center stage during development, and the deep perturbation of signaling consequent to its dysregulation in cancer reveals the multiplicity and complexity underlying its function. In [...] Read more.
The Eph receptors represent the largest group among Receptor Tyrosine kinase (RTK) families. The Eph/ephrin signaling axis plays center stage during development, and the deep perturbation of signaling consequent to its dysregulation in cancer reveals the multiplicity and complexity underlying its function. In the last decades, they have emerged as key players in solid tumors, including colorectal cancer (CRC); however, what causes EphA2 to switch between tumor-suppressive and tumor-promoting function is still an active theater of investigation. This review summarizes the recent advances in understanding EphA2 function in cancer, with detail on the molecular determinants of the oncogene-tumor suppressor switch function of EphA2. We describe tumor context-specific examples of EphA2 signaling and the emerging role EphA2 plays in supporting cancer—stem—cell-like populations and overcoming therapy-induced stress. In such a frame, we detail the interaction of the EphA2 and EGFR pathway in solid tumors, including colorectal cancer. We discuss the contribution of the EphA2 oncogenic signaling to the resistance to EGFR blocking agents, including cetuximab and TKIs. Full article
(This article belongs to the Special Issue EGFR Signaling in Cancer)
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