Special Issue "Epidermal Growth Factor Receptor Signaling in Cancer"

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

Deadline for manuscript submissions: 18 June 2019

Special Issue Editors

Guest Editor
Prof. Dr. Paul J. Higgins

Professor and Chair, Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, New York 12208, USA
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Interests: EGFR transactivation; TGF-β signaling; gene regulation; tumor progression; fibroproliferative disease; EMT; skin cancer; cell motility; PAI-1
Guest Editor
Dr. Rohan Samarakoon

Assistant Professor, Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, New York 12208, USA
Website | E-Mail
Interests: hippo signaling; renal fibrosis; kidney cancer; EGFR transactivation; non-SMAD TGF-β pathway; tumor suppressor deregulation in fibrosis

Special Issue Information

Dear Colleagues,

The epidermal growth factor receptor (EGFR) is a major contributor to tumorigenesis and an important therapeutic target against cancer progression. EGFR and its ligands are often over-expressed in human carcinomas. Amplification of the EGFR gene, mutations within the EGFR tyrosine kinase domain and dysregulated signaling occur in various human epithelial malignancies impacting tumor cell proliferation, transformation, plasticity, migration, survival and metastasis. Emerging studies also recognize the involvement of this tyrosine kinase receptor in drug resistance, pathologic cross-talk with other growth factor signaling pathways and in promoting inflammatory, angiogenic, fibrotic and mechanical changes in the tumor microenvironment, facilitating oncogenic behavior. EGFR transactivation by various cytokines and growth factors including TGF-β, PDGF, TNF-α and endothelin, as well as TLR4 ligands, further underscore the complexity of engaged networks that dictate tumor cell phenotype and may shed light on the basis for the limited clinical utility of available EGFR inhibitors in halting cancer progression. The purpose of this Special Issue is to explore the expanding diversity of mechanisms that regulate EGFR activation and signaling in human cancer that may provide new opportunities for personalized anti-cancer therapy. This Special Issue welcomes both review, as well as original research articles, by 18 June 2019.

Prof. Dr. Paul J. Higgins
Dr. Rohan Samarakoon
Guest Editors

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.

Keywords

  • EGFR in cell transformation
  • tumor progression
  • signaling
  • mutations
  • human cancers
  • EGFR pathway cross-talk
  • EGFR transactivation
  • EGFR inhibitors
  • drug resistance

Published Papers (5 papers)

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Research

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Open AccessArticle Nicotine Induces Resistance to Erlotinib Therapy in Non-Small-Cell Lung Cancer Cells Treated with Serum from Human Patients
Cancers 2019, 11(3), 282; https://doi.org/10.3390/cancers11030282
Received: 20 February 2019 / Accepted: 25 February 2019 / Published: 27 February 2019
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Abstract
Previously, we reported that nicotine reduces erlotinib sensitivity in a xenograft model of PC9, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitive non-small-cell lung cancer cell line. The present study examined whether smoking induces erlotinib resistance in vitro. We assessed resistance to EGFR-TKIs [...] Read more.
Previously, we reported that nicotine reduces erlotinib sensitivity in a xenograft model of PC9, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitive non-small-cell lung cancer cell line. The present study examined whether smoking induces erlotinib resistance in vitro. We assessed resistance to EGFR-TKIs by treating cancer cell lines with erlotinib, afatinib, or osimertinib, and serum collected from smokers within 30 min of smoking and that from a non-smoker as a control. We also assessed erlotinib resistance by treating PC9 cells exposed to serum from a smoker or a non-smoker, or serum from an erlotinib user. Treatment of the cancer cell lines with serum from smokers induced significant erlotinib resistance, compared with the control (p < 0.05). Furthermore, serum samples with a high concentration of cotinine (a nicotine exposure indicator) demonstrated stronger erlotinib resistance than those with low concentrations. Similar to the observations with erlotinib treatment of cell lines, the analysis of serum from erlotinib users revealed that smokers demonstrated significantly reduced sensitivity to erlotinib (p < 0.001). In conclusion, our present results support the hypothesis that smoking contributes to resistance to erlotinib therapy in non-small-cell lung cancer. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)
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Open AccessArticle Overcoming Intrinsic and Acquired Cetuximab Resistance in RAS Wild-Type Colorectal Cancer: An In Vitro Study on the Expression of HER Receptors and the Potential of Afatinib
Received: 4 December 2018 / Revised: 8 January 2019 / Accepted: 14 January 2019 / Published: 15 January 2019
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Abstract
The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the [...] Read more.
The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the clinic. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. The objective of this study was to investigate the expression of human epidermal growth factor (HER) receptors and the efficacy of afatinib, a second-generation irreversible EGFR-tyrosine kinase inhibitor, in RAS wild-type CRC cell lines with different cetuximab sensitivities. CRC cell lines with different sensitivities to cetuximab showed rather low EGFR expression but high HER2 and HER3 expression. These results were in line with the The Cancer Genome Atlas (TCGA) data from CRC patients, where higher mRNA levels of HER2 and HER3 were also detected compared to EGFR. Therefore, the targets of afatinib were indeed expressed on the CRC cell lines used in this study and in CRC patients. Furthermore, cetuximab resistance had no significant influence on the expression levels of HER receptors in CRC cell lines (p ≥ 0.652). This study also demonstrated that afatinib was able to induce a concentration-dependent cytotoxic effect in RAS wild-type CRC cell lines with different cetuximab sensitivities. Neither cetuximab resistance (p = 0.233) nor hypoxia (p = 0.157) significantly influenced afatinib’s cytotoxic effect. In conclusion, our preclinical data support the hypothesis that treatment with afatinib might be a promising novel therapeutic strategy for CRC patients experiencing intrinsic and acquired cetuximab resistance. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)
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Graphical abstract

Open AccessArticle Risk Factors for Severe Diarrhea with an Afatinib Treatment of Non-Small Cell Lung Cancer: A Pooled Analysis of Clinical Trials
Cancers 2018, 10(10), 384; https://doi.org/10.3390/cancers10100384
Received: 13 September 2018 / Revised: 3 October 2018 / Accepted: 10 October 2018 / Published: 15 October 2018
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Abstract
Afatinib is an effective therapy for metastatic non-small cell lung cancer (NSCLC) but it is associated with a relatively high incidence of severe diarrhea. The association between pre-treatment candidate predictors (age, sex, race, performance status, renal function, hemoglobin, and measures of body mass) [...] Read more.
Afatinib is an effective therapy for metastatic non-small cell lung cancer (NSCLC) but it is associated with a relatively high incidence of severe diarrhea. The association between pre-treatment candidate predictors (age, sex, race, performance status, renal function, hemoglobin, and measures of body mass) and severe (grade ≥ 3) diarrhea was evaluated using logistic regression with pooled individual participant data from seven clinical studies. A risk score was developed based on the count of major risk factors. Overall, 184 of 1151 participants (16%) experienced severe diarrhea with use of afatinib. Body weight, body mass index, and body surface area all exhibited a prominent non-linear association where risk increased markedly at the lower range (p < 0.005). Low weight (<45 kg), female sex, and older age (≥60 years) were identified as major independent risk factors (p < 0.01). Each risk factor was associated with a two-fold increase in the odds of severe diarrhea, and this was consistent between individuals commenced on 40 mg or 50 mg afatinib. A simple risk score based on the count of these risk factors identifies individuals at lowest and highest risk (C-statistic of 0.65). Risk of severe diarrhea for individuals commenced on 40 mg afatinib ranged from 6% for individuals with no risk factors to 33% for individuals with all three risk factors. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)
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Open AccessArticle A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy
Cancers 2018, 10(10), 355; https://doi.org/10.3390/cancers10100355
Received: 30 July 2018 / Revised: 10 September 2018 / Accepted: 23 September 2018 / Published: 26 September 2018
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Abstract
Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells [...] Read more.
Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)
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Review

Jump to: Research

Open AccessReview Newer-Generation EGFR Inhibitors in Lung Cancer: How Are They Best Used?
Cancers 2019, 11(3), 366; https://doi.org/10.3390/cancers11030366
Received: 15 January 2019 / Revised: 4 March 2019 / Accepted: 4 March 2019 / Published: 15 March 2019
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Abstract
The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, [...] Read more.
The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, double-blind trial of treatment-naïve patients with EGFR mutant NSCLC, osimertinib was compared to standard-of-care EGFR TKIs (i.e., erlotinib or gefinitib) in the first-line setting. Osimertinib demonstrated improvement in median progression-free survival (18.9 months vs. 10.2 months; hazard ratio 0.46; 95% CI, 0.37 to 0.57; p < 0.001) and a more favorable toxicity profile due to its lower affinity for wild-type EGFR. Furthermore, similar to later-generation anaplastic lymphoma kinase (ALK) inhibitors, osimertinib has improved efficacy against brain metastases. Despite this impressive effect, the optimal sequencing of osimertinib, whether in the first line or as subsequent therapy after the failure of earlier-generation EGFR TKIs, is not clear. Because up-front use of later-generation TKIs may result in the inability to use earlier-generation TKIs, this treatment paradigm must be evaluated carefully. For EGFR mutant NSCLC, considerations include the incidence of T790M resistance mutations, quality of life, whether there is a potential role for earlier-generation TKIs after osimertinib failure, and overall survival. This review explores these issues for EGFR inhibitors and other molecularly targeted therapies. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)
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