Mer590, a novel monoclonal antibody targeting MER receptor tyrosine kinase, decreases colony formation and increases chemosensitivity in non-small cell lung cancer
| Autor: | Rachel M. A. Linger, Deborah DeRyckere, Douglas K. Graham, Gregory Kirkpatrick, Kurtis D. Davies, Rebecca A. Cohen, Christopher T. Cummings, H. Shelton Earp, Susan Sather |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Lung Neoplasms medicine.medical_treatment Monoclonal Antibody Drug Resistance Down-Regulation Apoptosis C-Mer Tyrosine Kinase NSCLC Receptor tyrosine kinase Targeted therapy Carboplatin chemistry.chemical_compound Internal medicine Carcinoma Non-Small-Cell Lung Cell Line Tumor Proto-Oncogene Proteins medicine Humans Molecular Targeted Therapy RNA Small Interfering Lung cancer Protein kinase B Protein Kinase Inhibitors Chemosensitivity Tumor Stem Cell Assay Mitogen-Activated Protein Kinase 1 Hematology Mitogen-Activated Protein Kinase 3 biology c-Mer Tyrosine Kinase Cancer Antibodies Monoclonal Receptor Protein-Tyrosine Kinases Drug Synergism Targeted Therapy medicine.disease 3. Good health Gene Expression Regulation Neoplastic Oncogene Protein v-akt Oncology chemistry MER Cancer research biology.protein STAT6 Transcription Factor Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Christopher T. Cummings 1,* , Rachel M.A. Linger 1,4,* , Rebecca A. Cohen 1 , Susan Sather 1 , Gregory D. Kirkpatrick 1 , Kurtis D. Davies 1 , Deborah DeRyckere 1 , H. Shelton Earp 2,3 and Douglas K. Graham 1 1 Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA 2 Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA 3 Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 4 Department of Biomedical Sciences, Rocky Vista University College of Osteopathic Medicine, Parker, CO, USA * These authors contributed equally to this work Correspondence: Douglas K. Graham, email: // Keywords : MER, NSCLC, Monoclonal Antibody, Chemosensitivity, Targeted Therapy Received : May 19, 2014 Accepted : June 24, 2014 Published : June 26, 2014 Abstract The successes of targeted therapeutics against EGFR and ALK in non-small cell lung cancer (NSCLC) have demonstrated the substantial survival gains made possible by precision therapy. However, the majority of patients do not have tumors with genetic alterations responsive to these therapies, and therefore identification of new targets is needed. Our laboratory previously identified MER receptor tyrosine kinase as one such potential target. We now report our findings targeting MER with a clinically translatable agent – Mer590, a monoclonal antibody specific for MER. Mer590 rapidly and robustly reduced surface and total MER levels in multiple cell lines. Treatment reduced surface MER levels by 87%, and this effect was maximal within four hours. Total MER levels were also dramatically reduced, and this persisted for at least seven days. Mechanistically, MER down-regulation was mediated by receptor internalization and degradation, leading to inhibition of downstream signaling through STAT6, AKT, and ERK1/2. Functionally, this resulted in increased apoptosis, increased chemosensitivity to carboplatin, and decreased colony formation. In addition to carboplatin, Mer590 interacted cooperatively with shRNA-mediated MER inhibition to augment apoptosis. These data demonstrate that MER inhibition can be achieved with a monoclonal antibody in NSCLC. Optimization toward a clinically available anti-MER antibody is warranted. |
| Databáze: | OpenAIRE |
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