Occur Interestingly, mutations in PTEN gene somatic Association with BRAF mutations, but not RNA, suggesting activation of the double-track by comparison Changes AG-490 in NRAS alone or the combination of PTEN and BRAF.25, 44 on the other hand can be accomplished AKT an oncogene that encodes a kinase, the hot th Frequently deregulated in human activated cancers.45 There are three isoforms of Akt and AKT3 isoform in most melanoma.37 overexpression of phospho AKT, generally with an increased FITTINGS number of gene copies is associated is in a green larger proportion of melanomas seen and melanoma metastases nevi37, 45, and may, with the progress more tt and shorter survival time of patients with melanoma.46 inhibition AKT3 using a small interfering RNA or increased hte activation of apoptosis associated stimulated PTEN in melanoma cell lines, AKT to a function in apoptotic melanoma.
37 is to aim in cell line in vitro and in vivo studies in mouse xenograft and Afatinib AKT3 simultaneously with V600E BRAF siRNA resulted in increased FITTINGS apoptosis, and decreased proliferation support the relevance of these two signaling pathways in c melanoma.47 KIT RTK also contributing to the pathogenesis of a subset of melanoma, or that do not harbor NRAS BRAF mutations. c KIT activates several signaling cascades, including normal MAPK, PI3K/AKT / mTOR and microphthalmia associated transcription factor pathways.48, 49 c KIT signaling is necessary for the differentiation, proliferation and migration of normal melanocytes. c mutations of KIT and / or increased She hen the number of copies in melanomas of the mucosa has been identified, and chronic acral sun businesswoman digter skin.
50 induced point mutations in the gene result in constitutive activation of the downstream effectors of important signaling pathways in melanoma cells cells.51, 52 Although the H Frequency of changes KIT c is reported to be lower in Chinese, Korean and Australian cohorts53 55 compared to Western patients were such aberrations in patients with non-Chinese businesswoman identified chronic sun damaged skin and melanoma of unknown primary.54 geographic variability t in pr predisposing risk factors low Stichprobengr s study, the incomplete test’s full c-kit gene and criteria for solar elastosis, the marker of chronic Sonnebesch ending explained utern the apparent variation of the KIT mutation frequencies between populations.
The above laboratory and clinical studies best Term the importance of the activation of KIT and c components PI3K and MAPK pathways for pathogenesis of malignant melanoma. On the basis of these findings, the activation by mutations that activate RNA both PI3K and MAPK, or simultaneous BRAF mutations with limited Nkter function of PTEN or AKT, or c KIT mutations occur. Although these are not the only changes That contribute to the pathogenesis of malignant melanoma, provide clinical and laboratory findings first reason for the study of specific agents and combinations in patients with melanoma. M Possible targeted therapies for patients with advanced melanoma agents targeting the MAPK agents targeting the MAPK pathway are the first small molecule kinase inhibitor to demonstrate a clinical benefit for patients with melanoma. Agents entered clinical trials k Can in those relatively specific for mutated BRAF and / or BRAF, non-specific inhibitors of RAF and MEK inhibitors are to be grouped.