دورية أكاديمية
Combination of pan-RAF and MEK inhibitors in NRAS mutant melanoma
| العنوان: | Combination of pan-RAF and MEK inhibitors in NRAS mutant melanoma |
|---|---|
| المؤلفون: | Atefi, Mohammad, Titz, Bjoern, Avramis, Earl, Ng, Charles, Wong, Deborah JL, Lassen, Amanda, Cerniglia, Michael, Escuin-Ordinas, Helena, Foulad, David, Comin-Anduix, Begonya, Graeber, Thomas G, Ribas, Antoni |
| المصدر: | Molecular Cancer, vol 14, iss 1 |
| بيانات النشر: | eScholarship, University of California |
| سنة النشر: | 2015 |
| المجموعة: | University of California: eScholarship |
| مصطلحات موضوعية: | Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Apoptosis, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cyclin D1, Cyclin D3, GTP Phosphohydrolases, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, MAP Kinase Signaling System, Melanoma, Membrane Proteins, Mutation, Signal Transduction, Transcription, Genetic, raf Kinases, NRAS, MAPK, MEK inhibitor, pan-RAF inhibitor |
| الوصف: | BackgroundApproximately 20% of melanomas contain a mutation in NRAS. However no direct inhibitor of NRAS is available. One of the main signaling pathways downstream of NRAS is the MAPK pathway. In this study we investigated the possibility of blocking oncogenic signaling of NRAS by inhibiting two signaling points in the MAPK pathway.MethodsFourteen NRAS mutated human melanoma cell lines were treated with a pan-RAF inhibitor (PRi, Amgen Compd A), a MEK inhibitor (MEKi, trametinib) or their combination and the effects on proliferation, cell cycle progression, apoptosis, transcription profile and signaling of the cells were investigated.ResultsThe majority of the cell lines showed a significant growth inhibition, with high levels of synergism of the PRi and MEKi combination. Sensitive cell lines showed induction of apoptosis by the combination treatment and there was a correlation between p-MEK levels and synergistic effect of the combination treatment. Proliferation of sensitive cell lines was blocked by the inhibition of the MAPK pathway, which also blocked expression of cyclin D1. However, in resistant cell lines, proliferation was blocked by combined inhibition of the MAPK pathway and cyclin D3, which is not regulated by the MAPK pathway. Resistant cell lines also showed higher levels of p-GSK3β and less perturbation of the apoptotic profile upon the treatment in comparison with the sensitive cell lines.ConclusionsThe combination of PRi + MEKi can be an effective regimen for blocking proliferation of NRAS mutant melanomas when there is higher activity of the MAPK pathway and dependence of proliferation and survival on this pathway. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| العلاقة: | qt15p746hr; https://escholarship.org/uc/item/15p746hrTest |
| الإتاحة: | https://escholarship.org/uc/item/15p746hrTest |
| حقوق: | public |
| رقم الانضمام: | edsbas.C569D1C9 |
| قاعدة البيانات: | BASE |
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edsbas BASE edsbas.C569D1C9 862 3 Academic Journal academicJournal 862.1474609375 |
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However no direct inhibitor of NRAS is available. One of the main signaling pathways downstream of NRAS is the MAPK pathway. In this study we investigated the possibility of blocking oncogenic signaling of NRAS by inhibiting two signaling points in the MAPK pathway.MethodsFourteen NRAS mutated human melanoma cell lines were treated with a pan-RAF inhibitor (PRi, Amgen Compd A), a MEK inhibitor (MEKi, trametinib) or their combination and the effects on proliferation, cell cycle progression, apoptosis, transcription profile and signaling of the cells were investigated.ResultsThe majority of the cell lines showed a significant growth inhibition, with high levels of synergism of the PRi and MEKi combination. Sensitive cell lines showed induction of apoptosis by the combination treatment and there was a correlation between p-MEK levels and synergistic effect of the combination treatment. Proliferation of sensitive cell lines was blocked by the inhibition of the MAPK pathway, which also blocked expression of cyclin D1. However, in resistant cell lines, proliferation was blocked by combined inhibition of the MAPK pathway and cyclin D3, which is not regulated by the MAPK pathway. 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