Abstract
A new era in lung cancer targeted therapy arrived with the discovery of a subset of lung adenocarcinomas harboring activating mutations of the epidermal growth factor receptor (EGFR), whose tyrosine kinase activity can be selectively blocked by small molecule pharmaceuticals referred as tyrosine kinase inhibitors (TKIs). This was the starting point for a less toxic and more effective treatment strategy for a disease that has historically presented as chemorefractory and highly lethal. In spite of this progress, only 80% of the patients treated with this class of compounds will obtain a clinical benefit, of variable magnitude and duration, with remaining patients being primarily refractory to the treatment. Moreover, responding tumors will eventually develop acquired resistance to TKIs and progress to more advanced stages. In this review we summarize the current knowledge with regard to the mechanisms leading to tumor regression and the modifiers of this primary response that determine significant variability in sensitivity of tumors harboring EGFR activating mutations, ranging from complete remission to primary refractoriness. We also analyze the mechanisms of secondary resistance and the strategies the scientific community is exploring in order to overcome these barriers.
Keywords: Primary resistance, secondary resistance, refractory, sensitivity, erlotinib, gefitinib, afatinib.
Current Pharmaceutical Design
Title:Signaling Pathways Modulating Dependence of Lung Cancer on Mutant Epidermal Growth Factor Receptor and Mechanisms of Intrinsic and Acquired Resistance to Tyrosine Kinase Inhibitors
Volume: 20 Issue: 24
Author(s): Luciano Wannesson, Santiago Viteri, Carlota Costa, Niki Karachaliou, Miguel Angel Molina-Vila and Rafael Rosell
Affiliation:
Keywords: Primary resistance, secondary resistance, refractory, sensitivity, erlotinib, gefitinib, afatinib.
Abstract: A new era in lung cancer targeted therapy arrived with the discovery of a subset of lung adenocarcinomas harboring activating mutations of the epidermal growth factor receptor (EGFR), whose tyrosine kinase activity can be selectively blocked by small molecule pharmaceuticals referred as tyrosine kinase inhibitors (TKIs). This was the starting point for a less toxic and more effective treatment strategy for a disease that has historically presented as chemorefractory and highly lethal. In spite of this progress, only 80% of the patients treated with this class of compounds will obtain a clinical benefit, of variable magnitude and duration, with remaining patients being primarily refractory to the treatment. Moreover, responding tumors will eventually develop acquired resistance to TKIs and progress to more advanced stages. In this review we summarize the current knowledge with regard to the mechanisms leading to tumor regression and the modifiers of this primary response that determine significant variability in sensitivity of tumors harboring EGFR activating mutations, ranging from complete remission to primary refractoriness. We also analyze the mechanisms of secondary resistance and the strategies the scientific community is exploring in order to overcome these barriers.
Export Options
About this article
Cite this article as:
Wannesson Luciano, Viteri Santiago, Costa Carlota, Karachaliou Niki, Molina-Vila Angel Miguel and Rosell Rafael, Signaling Pathways Modulating Dependence of Lung Cancer on Mutant Epidermal Growth Factor Receptor and Mechanisms of Intrinsic and Acquired Resistance to Tyrosine Kinase Inhibitors, Current Pharmaceutical Design 2014; 20 (24) . https://dx.doi.org/10.2174/13816128113196660758
DOI https://dx.doi.org/10.2174/13816128113196660758 |
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
-
Cruciferous Plants: Phytochemical Toxicity Versus Cancer Chemoprotection
Mini-Reviews in Medicinal Chemistry The Optimal Diagnosis of Urothelial Carcinoma of the Bladder
Current Cancer Therapy Reviews Natural and Synthetic Retinoids in Prostate Cancer
Current Pharmaceutical Design Reversion of Multidrug Resistance in Tumor By Biocompatible Nanomaterials
Mini-Reviews in Medicinal Chemistry Nanoparticle Delivery Systems for DNA/RNA and their Potential Applications in Nanomedicine
Current Topics in Medicinal Chemistry Alteration of Ceramide 1-O-Functionalization as a Promising Approach for Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Management of Inflammatory Bowel Disease Patients with a Cancer History
Current Drug Targets Novel Series of Coumarinyl Substituted-thiazolidin-2,4-dione Analogs as Anticancer Agents: Design, Synthesis, Spectral Studies and Cytotoxicity Evaluation
Anti-Cancer Agents in Medicinal Chemistry Radioiodinated Ginger Compounds (6-gingerol and 6-shogaol) and Incorporation Assays on Breast Cancer Cells
Anti-Cancer Agents in Medicinal Chemistry Antibody-Based Targeted Interventions for the Diagnosis and Treatment of Skin Cancers
Anti-Cancer Agents in Medicinal Chemistry Role of Alterations in the Apoptotic Machinery in Sensitivity of Cancer Cells to Treatment
Current Pharmaceutical Design Receptor Tryosine Kinase Inhibitors as Potent Weapons in War Against Cancers
Current Pharmaceutical Design The Inhibitory Effect of Cyclosporine A and Prednisolone on Both Cytotoxic CD8+ T Cells and CD4+CD25+ Regulatory T Cells
Current Signal Transduction Therapy TGF-β Pathway as a Therapeutic Target in Bone Metastases
Current Pharmaceutical Design In-silico Study to Identify Dietary Molecules as Potential SARS-CoV-2 Agents
Letters in Drug Design & Discovery New Chalcones Containing 5-Fluorouracil Exhibiting in vitro Anti-Cancer Activity
Letters in Organic Chemistry Chemokines as Pharmacological Targets
Mini-Reviews in Medicinal Chemistry DNA Drug Design for Cancer Therapy
Current Pharmaceutical Design Leveraging Cell Cycle Analysis in Anticancer Drug Discovery to Identify Novel Plasmodial Drug Targets
Infectious Disorders - Drug Targets A Mini-Review on Nano Technology in the Tumour Targeting Strategies: Drug Delivery to Cancer Cells
Anti-Cancer Agents in Medicinal Chemistry