Abstract
Background: The frequency of pro-oncogenic mutations and development of drug resistance are major challenges for successful Ras-related cancer treatment. Novel targets in the Ras-signaling pathway may address these challenges. Cell division cycle protein 42 (Cdc42) is a classical member of the Rho family of small GTPases in the Ras oncogene superfamily. Enhanced Cdc42-signaling facilitates Ras-mediated cellular transformation, tumorigenesis, and metastasis. Cdc42, Ras, and EGFR are involved in an activation loop that prolongs their signaling. This review evaluates the benefits of targeting Cdc42 signaling as an anti-Ras cancer target.
Methods: We review the link between Ras and Cdc42 and summarize the roles of Cdc42 and select effectors in cancers. We discuss the discovery/development of Cdc42-signaling modulators and highlight studies that report the inhibition of the Cdc42-signaling pathway in several Ras-related cancer cell lines.
Results: Compared to EGFR and Ras, mutations that lead to the prolonged activation of Cdc42 are less common. Activation of upstream signals, changes in regulator expression, and alterations of Cdc42 protein expression play an important role in regulating Cdc42 activity. Eight selected effectors/adaptors of Cdc42 play a role in oncogenic Ras signaling. Of the fourteen natural and synthetic Cdc42 inhibitors discussed, eight small molecule inhibitors of Cdc42 have been used effectively in Ras-related cancer lines derived from breast, colon, lung, and pancreatic cancer.
Conclusions: Cdc42 is a putative therapeutic target in Ras-related cancers since Cdc42 functions downstream of EGFR and Ras, Cdc42 promotes/activates EGFR and Ras signaling, and Cdc42 inhibition in Ras-related cancers elicits anticancer effects.
Keywords: Cdc42, Ras, Rho GTPases, drug design, drug development, cancer therapy, lead optimization.
Current Medicinal Chemistry
Title:Cdc42 Signaling Pathway Inhibition as a Therapeutic Target in Ras- Related Cancers
Volume: 24 Issue: 32
Author(s): Byron J. Aguilar*, Huchen Zhou and Qun Lu *
Affiliation:
- Department of Anatomy & Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC,United States
- Department of Anatomy & Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC,United States
Keywords: Cdc42, Ras, Rho GTPases, drug design, drug development, cancer therapy, lead optimization.
Abstract: Background: The frequency of pro-oncogenic mutations and development of drug resistance are major challenges for successful Ras-related cancer treatment. Novel targets in the Ras-signaling pathway may address these challenges. Cell division cycle protein 42 (Cdc42) is a classical member of the Rho family of small GTPases in the Ras oncogene superfamily. Enhanced Cdc42-signaling facilitates Ras-mediated cellular transformation, tumorigenesis, and metastasis. Cdc42, Ras, and EGFR are involved in an activation loop that prolongs their signaling. This review evaluates the benefits of targeting Cdc42 signaling as an anti-Ras cancer target.
Methods: We review the link between Ras and Cdc42 and summarize the roles of Cdc42 and select effectors in cancers. We discuss the discovery/development of Cdc42-signaling modulators and highlight studies that report the inhibition of the Cdc42-signaling pathway in several Ras-related cancer cell lines.
Results: Compared to EGFR and Ras, mutations that lead to the prolonged activation of Cdc42 are less common. Activation of upstream signals, changes in regulator expression, and alterations of Cdc42 protein expression play an important role in regulating Cdc42 activity. Eight selected effectors/adaptors of Cdc42 play a role in oncogenic Ras signaling. Of the fourteen natural and synthetic Cdc42 inhibitors discussed, eight small molecule inhibitors of Cdc42 have been used effectively in Ras-related cancer lines derived from breast, colon, lung, and pancreatic cancer.
Conclusions: Cdc42 is a putative therapeutic target in Ras-related cancers since Cdc42 functions downstream of EGFR and Ras, Cdc42 promotes/activates EGFR and Ras signaling, and Cdc42 inhibition in Ras-related cancers elicits anticancer effects.
Export Options
About this article
Cite this article as:
Aguilar J. Byron *, Zhou Huchen and Lu Qun *, Cdc42 Signaling Pathway Inhibition as a Therapeutic Target in Ras- Related Cancers, Current Medicinal Chemistry 2017; 24 (32) . https://dx.doi.org/10.2174/0929867324666170602082956
DOI https://dx.doi.org/10.2174/0929867324666170602082956 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Engineered Polymer Nanoplatforms for Targeted Tumor Cells and Controlled Release Cargos to Enhance Cancer Treatment
Current Medicinal Chemistry Histone Methylation and Transcriptional Regulation in Cardiovascular Disease
Cardiovascular & Hematological Disorders-Drug Targets Strategy of Cancer Targeting Gene-Viro-Therapy (CTGVT) a Trend in Both Cancer Gene Therapy and Cancer Virotherapy
Current Pharmaceutical Biotechnology Regulation of Foxo-Dependent Transcription by Post-Translational Modifications
Current Drug Targets Lipid Nanoparticles to Deliver miRNA in Cancer
Current Pharmaceutical Biotechnology Evidence for the Involvement of Resistin in Inflammation and Cardiovascular Disease
Current Diabetes Reviews Targeted Radionuclide Therapy - An Overview
Current Radiopharmaceuticals Better Targeting Melanoma: Options Beyond Surgery and Conventional Chemotherapy
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Notch Signalling Pathways and Their Importance in the Treatment of Cancers
Current Drug Targets Essential Role of Gli Proteins in Glioblastoma Multiforme
Current Protein & Peptide Science Pharmacokinetics-Pharmacology Disconnection of Herbal Medicines and its Potential Solutions with Cellular Pharmacokinetic-Pharmacodynamic Strategy
Current Drug Metabolism Biomaterial and Mesenchymal Stem Cell for Articular Cartilage Reconstruction
Current Stem Cell Research & Therapy The Significance of Transferrin Receptors in Oncology: the Development of Functional Nano-based Drug Delivery Systems
Current Drug Delivery Proline Oxidase (POX) as A Target for Cancer Therapy
Current Drug Targets Targeting the Eph-ephrin System with Protein-Protein Interaction (PPI) Inhibitors
Current Drug Targets The Potential Clinical Impact of Probiotic Treatment for the Prevention and/or Anti-Inflammatory Therapeutic Effect Against Radiation Induced Intestinal Mucositis. A Review
Recent Patents on Inflammation & Allergy Drug Discovery Current Strategies for Probing Substrate Specificity of Proteases
Current Medicinal Chemistry OX40 and OX40L Interaction in Cancer
Current Medicinal Chemistry Proteome Analysis in Hematology Using Capillary Electrophoresis Coupled On-Line to Mass Spectrometry
Mini-Reviews in Medicinal Chemistry Targeting DNA Topoisomerase I with Non-Camptothecin Poisons
Current Medicinal Chemistry