Abstract
Approximately 20-30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Trastuzumab (Herceptin) is a clinically approved anti-HER2 monoclonal antibody. Many patients with HER2-overexpressing metastatic breast cancer respond to trastuzumab; however, a subset display primary drug resistance. In addition, many patients who initially respond to trastuzumab ultimately develop disease progression. Multiple molecular mechanisms contributing to trastuzumab resistance have been proposed in the literature. These mechanisms include cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for insulin-like growth factor-I, vascular endothelial growth factor, and transforming growth factor beta. The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor cross-talk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer.
Keywords: Breast cancer, erbB2, Her2, Herceptin, resistance, Trastuzumab, cross-talk, lapatinib, pertuzumab, IGF-IR, VEGF, TGF beta, FAK
Current Medicinal Chemistry
Title: Pharmacological Strategies to Overcome HER2 Cross-Talk and Trastuzumab Resistance
Volume: 19 Issue: 7
Author(s): R. Nahta
Affiliation:
Keywords: Breast cancer, erbB2, Her2, Herceptin, resistance, Trastuzumab, cross-talk, lapatinib, pertuzumab, IGF-IR, VEGF, TGF beta, FAK
Abstract: Approximately 20-30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Trastuzumab (Herceptin) is a clinically approved anti-HER2 monoclonal antibody. Many patients with HER2-overexpressing metastatic breast cancer respond to trastuzumab; however, a subset display primary drug resistance. In addition, many patients who initially respond to trastuzumab ultimately develop disease progression. Multiple molecular mechanisms contributing to trastuzumab resistance have been proposed in the literature. These mechanisms include cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for insulin-like growth factor-I, vascular endothelial growth factor, and transforming growth factor beta. The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor cross-talk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer.
Export Options
About this article
Cite this article as:
Nahta R., Pharmacological Strategies to Overcome HER2 Cross-Talk and Trastuzumab Resistance, Current Medicinal Chemistry 2012; 19 (7) . https://dx.doi.org/10.2174/092986712799320691
DOI https://dx.doi.org/10.2174/092986712799320691 |
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
-
Progress Towards Clinically Useful Aldosterone Synthase Inhibitors
Current Topics in Medicinal Chemistry Immunomodulation in Inflammatory Neuropathies: Rationale and Safety
Current Drug Safety The Role of 18 kDa Mitochondrial Translocator Protein (TSPO) in Programmed Cell Death, and Effects of Steroids on TSPO Expression
Current Molecular Medicine Patent Selections:
Recent Patents on Anti-Cancer Drug Discovery Photo- and Sono-Dynamic Therapy: A Review of Mechanisms and Considerations for Pharmacological Agents Used in Therapy Incorporating Light and Sound
Current Pharmaceutical Design Human Disease Modelling Techniques: Current Progress
Current Molecular Medicine The Boundary between Hypochondriasis, Personality Dysfunction, and Trauma
Current Psychiatry Reviews Cigarette Smoke Decreases Salivary 18 kDa Translocator Protein Binding Affinity – in Association with Oxidative Stress
Current Medicinal Chemistry Clinical Strategies for the Blockade of IL-18 in Inflammatory Bowel Diseases
Current Drug Targets Anti-Cancer Effect of Melatonin via Downregulation of Delta-like Ligand 4 in Estrogen-Responsive Breast Cancer Cells
Recent Patents on Anti-Cancer Drug Discovery An Overview of Nano Delivery Systems for Targeting RNA Interference-based Therapy in Ulcerative Colitis
Current Pharmaceutical Design Post-Transcriptional and Post-translational Regulation of Central Carbon Metabolic Enzymes in Cancer
Anti-Cancer Agents in Medicinal Chemistry Ginsenoside Rh2 Inhibits Migration of Lung Cancer Cells under Hypoxia via mir-491
Anti-Cancer Agents in Medicinal Chemistry Preclinical and Clinical Studies on the Use of Platinum Complexes for Breast Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry Bombacaceae Between the Ethnomedical Uses and Pharmacological Evidences: A Review
The Natural Products Journal Development of Vasculature Targeting Strategies for the Treatment of Chronic Inflammatory Diseases
Current Drug Targets - Inflammation & Allergy Choline Kinase Alpha Depletion Selectively Kills Tumoral Cells
Current Cancer Drug Targets When Neighbors Talk: Colon Cancer Cell Invasion and Tumor Microenvironment Myofibroblasts
Current Drug Targets The Epigenetic Modification of Epigallocatechin Gallate (EGCG) on Cancer
Current Drug Targets Molecular Imaging of Tumor Angiogenesis and Therapeutic Effects with Dual Bioluminescence
Current Pharmaceutical Biotechnology