However, no effective direct inhibitor of mutated NRAS is available. In melanomas with BRAF V600 mutation, the MAPK pathway, and therefore the growth of melanoma cells, can be efficiently blocked by BRAF inhibitors such as vemurafenib or dabrafenib. Over activity of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is the hallmark of the majority of melanomas, which is frequently due to mutations in BRAF or NRAS in approximately 50% and 20% of cases, respectively. 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. 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. 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. Proliferation of sensitive cell lines was blocked by the inhibition of the MAPK pathway, which also blocked expression of cyclin D1. 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. The majority of the cell lines showed a significant growth inhibition, with high levels of synergism of the PRi and MEKi combination. Methodsįourteen 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. In this study we investigated the possibility of blocking oncogenic signaling of NRAS by inhibiting two signaling points in the MAPK pathway. One of the main signaling pathways downstream of NRAS is the MAPK pathway.
However no direct inhibitor of NRAS is available.
Approximately 20% of melanomas contain a mutation in NRAS.
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