Combination of pan-RAF and MEK inhibitors in NRAS mutant melanoma
| العنوان: | Combination of pan-RAF and MEK inhibitors in NRAS mutant melanoma |
|---|---|
| المؤلفون: | Earl Avramis, Charles Ng, Michael Cerniglia, Helena Escuin-Ordinas, Amanda Lassen, Bjoern Titz, Begonya Comin-Anduix, Mohammad Atefi, Thomas G. Graeber, Antoni Ribas, Deborah J.L. Wong, David Foulad |
| المصدر: | Molecular cancer, vol 14, iss 1 Molecular Cancer |
| بيانات النشر: | Springer Science and Business Media LLC, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | MAPK/ERK pathway, Neuroblastoma RAS viral oncogene homolog, Cancer Research, Transcription, Genetic, Apoptosis, GTP Phosphohydrolases, Glycogen Synthase Kinase 3, 0302 clinical medicine, Cyclin D1, Cyclin D3, Melanoma, Cancer, Trametinib, 0303 health sciences, Tumor, MEK inhibitor, Cell Cycle, 3. Good health, Oncology, 5.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Molecular Medicine, raf Kinases, Development of treatments and therapeutic interventions, Signal transduction, Transcription, Signal Transduction, MAP Kinase Signaling System, Oncology and Carcinogenesis, NRAS, Biology, Cell Line, 03 medical and health sciences, Genetic, Cell Line, Tumor, Humans, Oncology & Carcinogenesis, Cell Proliferation, 030304 developmental biology, Glycogen Synthase Kinase 3 beta, Research, Membrane Proteins, MAPK, Mutation, Cancer research, pan-RAF inhibitor |
| الوصف: | Background Approximately 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. Methods Fourteen 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. Results The 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. Conclusions The 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. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0293-5) contains supplementary material, which is available to authorized users. |
| وصف الملف: | application/pdf |
| تدمد: | 1476-4598 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e320a3c09cf525a3044f85b50b79be40Test https://doi.org/10.1186/s12943-015-0293-5Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e320a3c09cf525a3044f85b50b79be40 |
| قاعدة البيانات: | OpenAIRE |
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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. Methods Fourteen 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. Results The 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. Conclusions The 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. 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