Abstract
Conventional chemotherapeutic regimens have reached an efficacy plateau against most solid tumors and deal with significant toxicity. Recently, the goal of oncologic research to improve outcome and reduce treatment-related side-effects has led to the development of novel anticancer treatments targeting specific proteins or genes involved in cancer growth and progression. In particular, the tyrosine- kinase inhibitors (TKIs) gefitinib and erlotinib targeting the epidermal growth factor receptor (EGFR) have been approved for the treatment of non-small-cell lung cancer (NSCLC). Their clinical activity has been related to different clinical and biological parameters, such as the presence of activating mutations in the kinase domain of the target. Disappointingly, their clinical efficacy is limited by the development of resistance which is caused in more than 50% of the cases by the emergence of a secondary point-mutation (T790M) in the ATP-binding cleft of EGFR. Several novel EGFR inhibitors, able to covalently bind the target and prolong its inactivation, have been developed with the aim to overcome such resistance and are evaluated in ongoing clinical studies. However, not all clinical outcomes, including tolerability, are explained, and the identification/validation of novel biomarkers of sensitivity or resistance to such agents is a viable area of research to improve their clinical use. This review summarizes the current knowledge on the functional role of activating mutations of EGFR, pivotal primary/acquired resistance mechanisms as well as clinical data of small molecule EGFR-TKIs, and discusses the future of such therapeutic approach in NSCLC.
Keywords: EGFR, NSCLC, tyrosine kinase, gefitinib, erlotinib, acquired resistance, therapy, solid tumors, cancer, biomarkers
Current Pharmaceutical Design
Title:Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Current Status and Future Perspectives in the Development of Novel Irreversible Inhibitors for the Treatment of Mutant Non-small Cell Lung Cancer
Volume: 19 Issue: 5
Author(s): Elena Galvani, Roberta Alfieri, Elisa Giovannetti, Andrea Cavazzoni, Silvia La Monica, Maricla Galetti, Claudia Fumarola, Mara Bonelli, Marco Mor, Marcello Tiseo, Godefridus J. Peters, Pier Giorgio Petronini and Andrea Ardizzoni
Affiliation:
Keywords: EGFR, NSCLC, tyrosine kinase, gefitinib, erlotinib, acquired resistance, therapy, solid tumors, cancer, biomarkers
Abstract: Conventional chemotherapeutic regimens have reached an efficacy plateau against most solid tumors and deal with significant toxicity. Recently, the goal of oncologic research to improve outcome and reduce treatment-related side-effects has led to the development of novel anticancer treatments targeting specific proteins or genes involved in cancer growth and progression. In particular, the tyrosine- kinase inhibitors (TKIs) gefitinib and erlotinib targeting the epidermal growth factor receptor (EGFR) have been approved for the treatment of non-small-cell lung cancer (NSCLC). Their clinical activity has been related to different clinical and biological parameters, such as the presence of activating mutations in the kinase domain of the target. Disappointingly, their clinical efficacy is limited by the development of resistance which is caused in more than 50% of the cases by the emergence of a secondary point-mutation (T790M) in the ATP-binding cleft of EGFR. Several novel EGFR inhibitors, able to covalently bind the target and prolong its inactivation, have been developed with the aim to overcome such resistance and are evaluated in ongoing clinical studies. However, not all clinical outcomes, including tolerability, are explained, and the identification/validation of novel biomarkers of sensitivity or resistance to such agents is a viable area of research to improve their clinical use. This review summarizes the current knowledge on the functional role of activating mutations of EGFR, pivotal primary/acquired resistance mechanisms as well as clinical data of small molecule EGFR-TKIs, and discusses the future of such therapeutic approach in NSCLC.
Export Options
About this article
Cite this article as:
Galvani Elena, Alfieri Roberta, Giovannetti Elisa, Cavazzoni Andrea, La Monica Silvia, Galetti Maricla, Fumarola Claudia, Bonelli Mara, Mor Marco, Tiseo Marcello, J. Peters Godefridus, Giorgio Petronini Pier and Ardizzoni Andrea, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Current Status and Future Perspectives in the Development of Novel Irreversible Inhibitors for the Treatment of Mutant Non-small Cell Lung Cancer, Current Pharmaceutical Design 2013; 19 (5) . https://dx.doi.org/10.2174/1381612811306050818
DOI https://dx.doi.org/10.2174/1381612811306050818 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Dietary Phytochemicals in Chemoprevention of Cancer
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Exploring Confluence-Related Signalling to Modulate the Expression of Oct4 – A Role in Facilitating Mouse Somatic Cell Reprogramming?
Current Stem Cell Research & Therapy Biological Activity of Carotenoids: Its Implications in Cancer Risk and Prevention
Current Pharmaceutical Biotechnology Antitumor Activity of Polysaccharides: An Overview
Current Drug Targets Recent Developments of DNA Poisons - Human DNA Topoisomerase IIα Inhibitors - as Anticancer Agents
Current Pharmaceutical Design Characterization of Carbonic Anhydrase Isozyme Specific Inhibition by Sulfamated 2-Ethylestra Compounds
Letters in Drug Design & Discovery subject Index To Volume 1
Current Molecular Medicine Adenovirus-Based Cancer Gene Therapy
Current Gene Therapy High-Risk HPV/ErbB-2 Interaction on E-Cadherin/Catenin Regulation in Human Carcinogenesis
Current Pharmaceutical Design Nitric Oxide: Cancer Target or Anticancer Agent?
Current Cancer Drug Targets New Strategies in the Chemotherapy of Leukemia: Eradicating Cancer Stem Cells in Chronic Myeloid Leukemia
Current Cancer Drug Targets The Complex Airway in Childhood Asthma
Current Pediatric Reviews Combined Treatment with CCI779 and SB203580 Induces Cellular Senescence in Renal Cell Carcinoma Cell Line via p53 Pathway
Anti-Cancer Agents in Medicinal Chemistry TXNL1 Induces Apoptosis in Cisplatin Resistant Human Gastric Cancer Cell Lines
Current Cancer Drug Targets Prospective Plant Based Anticancer Lead Molecules
Current Topics in Medicinal Chemistry The Engaged Role of Tumor Microenvironment in Cancer Metabolism: Focusing on Cancer-Associated Fibroblast and Exosome Mediators
Anti-Cancer Agents in Medicinal Chemistry The Influence of Macrophages and the Tumor Microenvironment on Natural Killer Cells
Current Molecular Medicine Genetics of Serotonin Receptors and Depression: State of the Art
Current Drug Targets 1,3,4-Thiadiazole Based Anticancer Agents
Anti-Cancer Agents in Medicinal Chemistry Dual Targeting of Glioma U251 Cells with Nanoparticles Prevents Tumor Angiogenesis and Inhibits Tumor Growth
Current Neurovascular Research