Abstract
Background. We evaluated the mutation status of c-Met in small cell lung cancer (SCLC) and neuroendocrine tumors (NET), for which relatively limited therapeutic targets have been explored.
Materials and Methods. c-Met was re-sequenced using cell lines and clinical samples. For in vitro studies, DNA constructs containing a juxtamembrane domain (JMD) and tyrosine kinase domain (TKD) were generated. Detected mutations were introduced into the construct and effects on c-Met phosphorylation and interaction with tyrosine kinase inhibitor drugs BMS777607 and SU11274 were assessed.
Results. 97 specimens were analyzed: 13 SCLC and 2 pulmonary carcinoid cell lines, 46 SCLC and 36 NET clinical specimens. Mutations were only detected in the JMD. No mutations were detected in the TKD. Found mutations consisted of the previously reported R988C and T1010I mutations. One novel JMD mutation, P996S, was detected in a SCLC specimen. The mutation rate in SCLC cell lines was 25% (31% including a derivative cell line), and 6.5% in clinical specimens. The mutation rate in NET was 8.3%. In vitro, there were no differences between wild type, R988C or T1010I mutants regarding c-Met phosphorylation at Y1003, located in the JMD, and at Y1234/1235, located in the TKD. BMS777607 and SU11274 were shown to inhibit phosphorylation of c-Met in wild type and R988C and T1010I mutants in a similar fashion.
Conclusions. In SCLC and neuroendocrine tumors MET mutations are relatively rare. Detected mutations were located in the juxtamembrane domain and were of no functional relevance as they did not influence c-Met phosphorylation, regardless of TKI treatment.
Keywords: c-Met, mutation, neuroendocrine tumor, tyrosine kinase inhibitor, small cell lung cancer (SCLC), juxtamembrane domain (JMD), tyrosine kinase domain (TKD), phosphorylation, cell line, wild type
Current Pharmaceutical Design
Title:Detection and Therapeutic Implications of c-Met Mutations in Small Cell Lung Cancer and Neuroendocrine Tumors
Volume: 19 Issue: 5
Author(s): J. Voortman, T. Harada, R.P. Chang, J.K. Killian, M. Suuriniemi, W.I. Smith, P.S. Meltzer, M. Lucchi, Y. Wang and G. Giaccone
Affiliation:
Keywords: c-Met, mutation, neuroendocrine tumor, tyrosine kinase inhibitor, small cell lung cancer (SCLC), juxtamembrane domain (JMD), tyrosine kinase domain (TKD), phosphorylation, cell line, wild type
Abstract: Background. We evaluated the mutation status of c-Met in small cell lung cancer (SCLC) and neuroendocrine tumors (NET), for which relatively limited therapeutic targets have been explored.
Materials and Methods. c-Met was re-sequenced using cell lines and clinical samples. For in vitro studies, DNA constructs containing a juxtamembrane domain (JMD) and tyrosine kinase domain (TKD) were generated. Detected mutations were introduced into the construct and effects on c-Met phosphorylation and interaction with tyrosine kinase inhibitor drugs BMS777607 and SU11274 were assessed.
Results. 97 specimens were analyzed: 13 SCLC and 2 pulmonary carcinoid cell lines, 46 SCLC and 36 NET clinical specimens. Mutations were only detected in the JMD. No mutations were detected in the TKD. Found mutations consisted of the previously reported R988C and T1010I mutations. One novel JMD mutation, P996S, was detected in a SCLC specimen. The mutation rate in SCLC cell lines was 25% (31% including a derivative cell line), and 6.5% in clinical specimens. The mutation rate in NET was 8.3%. In vitro, there were no differences between wild type, R988C or T1010I mutants regarding c-Met phosphorylation at Y1003, located in the JMD, and at Y1234/1235, located in the TKD. BMS777607 and SU11274 were shown to inhibit phosphorylation of c-Met in wild type and R988C and T1010I mutants in a similar fashion.
Conclusions. In SCLC and neuroendocrine tumors MET mutations are relatively rare. Detected mutations were located in the juxtamembrane domain and were of no functional relevance as they did not influence c-Met phosphorylation, regardless of TKI treatment.
Export Options
About this article
Cite this article as:
Voortman J., Harada T., Chang R.P., Killian J.K., Suuriniemi M., Smith W.I., Meltzer P.S., Lucchi M., Wang Y. and Giaccone G., Detection and Therapeutic Implications of c-Met Mutations in Small Cell Lung Cancer and Neuroendocrine Tumors, Current Pharmaceutical Design 2013; 19 (5) . https://dx.doi.org/10.2174/1381612811306050833
DOI https://dx.doi.org/10.2174/1381612811306050833 |
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
-
Polymorphisms of Genes Encoding Phase I Enzymes in Mexican Americans – An Ethnic Comparison Study
Current Pharmacogenomics Applications of Mannich Reaction in Total Syntheses of Natural Products
Current Organic Chemistry New Generation of Liposomal Drugs for Cancer
Anti-Cancer Agents in Medicinal Chemistry Expression and Function of Kruppel Like-Factors (KLF) in Carcinogenesis
Current Genomics Detection of Clonal Immunoglobulin and T-Cell Receptor Gene Recombination in Hematological Malignancies: Monitoring Minimal Residual Disease
Cardiovascular & Hematological Disorders-Drug Targets Hypocholesterolemia
Current Vascular Pharmacology Will Antiangiogenic Agents be a Future for Mesothelioma Therapy?
Current Medicinal Chemistry Identification and Characterization of SNP Mutation in Genes Related to Non-small Cell Lung Cancer
Current Signal Transduction Therapy Advances in Sub-Micron Particle Based Aerosol Strategies for Efficient Systemic Delivery of Therapeutic Agents
Current Pharmaceutical Design The Anti-Cancer Activity of Noscapine: A Review
Recent Patents on Anti-Cancer Drug Discovery Neurodegenerative Disease: A Perspective on Cell-Based Therapy in the New Era of Cell-Free Nano-Therapy
Current Pharmaceutical Design Improved 3D-QSAR Prediction by Multiple Conformational Alignments and Molecular Docking Studies to Design and Discover HIV-I Protease Inhibitors
Current HIV Research Nanotechnologies for Anti-Inflammatory RNAi-Based Gene Silencing Strategies
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry The Many Faces of Glutathione Transferase Pi
Current Molecular Medicine Nucleic Acid Aptamers: Clinical Applications and Promising New Horizons
Current Medicinal Chemistry Drug Eluting Stents: Friend or Foe? A Review of Cellular Mechanisms Behind the Effects of Paclitaxel and Sirolimus Eluting Stents
Current Drug Metabolism The Role of Antihistamine Drugs in Allergic Disorders
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Molecular Targeting of Protein Kinases to Optimize Selectivity and Resistance Profiles of Kinase Inhibitors
Current Topics in Medicinal Chemistry Selected Attributes of Polyphenols in Targeting Oxidative Stress in Cancer
Current Topics in Medicinal Chemistry Current Advances in Clinical Trials for Rare Disease Populations: Spotlight on the Patient
Current Reviews in Clinical and Experimental Pharmacology