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Receptor Tyrosine Kinases as Drug Targets: Present Status and Future Directions

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A special issue of Applied Sciences (ISSN 2076-3417). This special issue belongs to the section "Applied Biosciences and Bioengineering".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 8740

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Special Issue Editor

Dr. John Patrick Alao

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Guest Editor

School of Health, Sports and Bioscience, University of East London, Stratford Campus, London E15 4LZ, UK
Interests: caffeine; schizosaccharomyces pombe; DNA damage, stress response; cell cycle; cell cycle checkpoints; cancer; cyclin D1; kinases, kinase inhibitors; molecular genetics; target of rapamycin; qRT-PCR; multiplex PCR; GST; molecular diagnostics; MASSarray; SARS-CoV-2

Special Issue Information

Dear Colleagues,

You are cordially invited to contribute to this Special Issue entitled “Receptor Tyrosine Kinases as Drug Targets: Present Status and Future Directions”—a research area that continues to draw considerable interest.

Receptor tyrosine kinases (RTKs) comprise about 58 members and share common structural motifs, including an extracellular ligand binding domain, a helix that transverses the cell membrane and an intracellular a regulatory juxtamembrane region, a kinase domain and a C- terminal domain. RTKs modulate diverse cellular processes whose deregulation has been implicated in diseases such as cancer, neurodegenerative diseases, heart disease, developmental disorders and substance abuse. In recent years, growing evidence for the role of collagen- binding RTKs in various disease processes has also been reported. While RTKs are generally viewed in the context of drug inhibition, particularly in cancer, recent studies have identified roles for RTK agonists particularly in the treatment of substance abuse disorders. Lastly, RTK ligands provide powerful chemical tools for analysing cellular signalling pathways. In this regard, photo-switchable inhibitors that can be activated at will are of crucial importance. This review aims to provide novel insights on the present status and future directions of RTKs as druggable targets.

You are cordially invited to contribute in these topics or novel ones of your choosing to this timely Special Edition.

Dr. John Patrick Alao
Guest Editor

Manuscript Submission Information

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Keywords

Receptor tyrosine kinase
Mutation
Cell signalling
Targeted therapy
Antagonist
Agonist
Molecular tools
Cancer
Neurodegenerative disease
Substance abuse

Published Papers (3 papers)

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Research

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21 pages, 12485 KiB

Open AccessArticle

Sensitivity of EGFR/HER-2 Positive Cells Isolated from Ascitic Fluid of Advanced Ovarian Cancer Patients to EGFR/HER-2 Inhibitors

by Kenny Chitcholtan, Dianne Harker, Bryony Simcock and Peter Sykes

Appl. Sci. 2020, 10(7), 2343; https://doi.org/10.3390/app10072343 - 29 Mar 2020

Cited by 2 | Viewed by 2659

Abstract

Background: advanced ovarian cancer often presents with ascites. These ascites contain small clusters of cancer cells, which may contribute greatly to the metastatic potential of ovarian cancer in the peritoneal cavity. Therefore, understanding the unique protein expressions of this cell population will provide vital information for the development of tailored, targeted treatment. In this study, we isolate floating ovarian cancer cells from ovarian cancer patient ascitic fluid and use these cells to document that the expression of EGFR/HER-2 proteins may be essential for the growth and survival of these floating cancer cell clusters. Methods: ascitic fluid-derived cells were isolated from ascitic fluid by using Ficoll separation. Cells were cultured in a non-adherent condition for six days. The protein level of EGFR, HER-2, AKT, and ERK and their phosphorylation in ovarian cancer cell lines were determined by immunofluorescence. The immunofluorescent staining for proteins presented in ascitic fluid-derived cells determined the intensity profile of each protein using Carl Zeiss Blue software. Results: Isolated ovarian cancer cells from ascitic fluid have a measurable level of EGFR and HER-2 proteins. The inhibition of EGFR and EGFR/HER-2 positive cells with gefitinib and canertinib selectively disrupts cell viability and the protein level of EGFR, HER-2, AKT and ERK and their respective phosphorylation status. In addition, the dual EGFR/HER-2 inhibitor canertinib demonstrates greater anti-tumour effects than gefitinib in EGFR/HER-2 positive cells. Conclusion: These studies reveal an important role of multiple activation of receptor tyrosine kinases in floating ovarian cancer cells, as well as the importance of a dual EGFR/HER-2 inhibitor used as alternative adjuvant therapy in advanced ovarian cancer patients. Full article

(This article belongs to the Special Issue Receptor Tyrosine Kinases as Drug Targets: Present Status and Future Directions)

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18 pages, 2107 KiB

Open AccessArticle

Expression of Insulin Receptor and c-MET Is Associated with Clinicopathologic Characteristics and Molecular Subtypes in Premenopausal Breast Cancer Patients

by Nehad M. Ayoub, Rami J. Yaghan, Alia H. Al-Mohtaseb, Najla Aldaoud, Ismail I. Matalka and Muwada E. Elhassan

Appl. Sci. 2020, 10(5), 1614; https://doi.org/10.3390/app10051614 - 29 Feb 2020

Cited by 2 | Viewed by 2250

Abstract

Receptor Tyrosine Kinases (RTKs) represent a class of transmembrane receptors known to play an important role in cancer development and progression. In this study, the expression of insulin receptor (IR) and the hepatocyte growth factor receptor (c-MET) was examined in breast cancer patients. Immunohistochemistry for IR and c-MET was performed on 71 cases of invasive breast cancer and expression scores were correlated with clinicopathologic characteristics and molecular subtypes and further stratified based on a menopausal status. Expression of IR was significantly associated with the tumor grade (p = 0.017) and estrogen receptor (ER) expression (p = 0.015). There was a significant positive correlation between IR and c-MET expression scores (rho = 0.458, p < 0.001). Among premenopausal cases, IR scores were significantly higher in patients with grade I/II disease (p = 0.025), ER-positive (p = 0.030), and progesterone receptor (PR)-positive carcinoma (p = 0.015). c-MET expression scores were significantly higher among premenopausal patients with ER-positive (p = 0.007) and PR-positive carcinoma (p = 0.024). IR expression scores were significantly different among molecular subtypes for all patients (p = 0.006) and among premenopausal cases (p = 0.035). c-MET expression was statistically different among molecular subtypes for premenopausal patients (p = 0.019). Survival analysis revealed that the expression status of IR and c-MET was not associated with overall survival. Our findings support a favorable prognostic value for IR and c-MET expression in premenopausal breast cancer patients. Full article

(This article belongs to the Special Issue Receptor Tyrosine Kinases as Drug Targets: Present Status and Future Directions)

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Review

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14 pages, 643 KiB

Open AccessReview

Targeted Therapy in Metastatic Bladder Cancer: Present Status and Future Directions

by Mathijs Scholtes, Maryam Akbarzadeh, Ellen Zwarthoff, Joost Boormans, Tokameh Mahmoudi and Tahlita Zuiverloon

Appl. Sci. 2020, 10(20), 7102; https://doi.org/10.3390/app10207102 - 13 Oct 2020

Cited by 6 | Viewed by 3367

Abstract

The recommended treatment for metastatic urothelial carcinoma (mUC) patients is platinum-based chemotherapy. Although initial response rates are moderate, the vast majority of patients experience a relapse due to chemoresistance and eventually succumb to their disease. Furthermore, platinum-based chemotherapy is toxic and approximately 30% of mUC patients are unfit for chemotherapy. Thus, there is a clear unmet need for novel, more efficacious treatment options in mUC with a safer toxicity profile. To propel the advancement of novel treatment options, we present a summary of key signaling pathways and molecular mechanisms that are known to be involved in bladder cancer tumorigenesis with a focus on promising candidate druggable molecular targets and innovative targeted therapies currently under clinical investigation. Targetable alterations were mainly described in fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (ErbB) tyrosine kinase receptor (RTK) families, downstream pathways, and chromatin remodelers, which are major bladder cancer driver genes. Drugs targeting the FGFR family members are emerging as personalized treatment options for selected mUC patients with tumor-specific FGFR alterations. The pan-FGFR inhibitor, erdafitinib, was first-in-class to receive U.S. Food and Drug Administration (FDA) approval in 2019, while inhibitors of ErbB family members have shown less potential. Antibody-drug conjugates (ADCs) are a class of targeted therapeutics that deliver cytotoxic drugs in close proximity to cancer cells by targeting RTKs or other transmembrane proteins. Enfortumab vedotin is the first-in-class ADC that was FDA approved for the treatment of locally advanced or mUC in 2019. Full article

(This article belongs to the Special Issue Receptor Tyrosine Kinases as Drug Targets: Present Status and Future Directions)

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