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• W2332593577 abstract "Purpose: The aims of this study were to investigate the correlation between MAPK activation and somatic mutation in GNAQ and GNA11 genes in uveal melanoma (UM) and to investigate the potential utility of MEK inhibition as a target for therapy of UM in tumors with GNAQ and GNA11 mutations. Methods: Sequencing and restriction fragment length polymorphism (RFLP) were utilized for detection of activating mutations in codon 209 of the GNAQ and GNA11 genes in 44 primary UMs. The expression of phospho p44/42 MAPK (pERK1/2) was assessed by immunohistochemistry in 44 UMs. In addition, the expression of pERK1/2 and pMEK 1/2 were studied using Western blot analysis in 17 primary UMs (14 with GNAQ or GNA11 mutations) and five UM cell lines (C918, 92.1, OCM3, MEL202, MEL270). Three of the UM cell lines (92.1, MEL202 and MEL270) have GNAQ codon 209 mutations. The effect of three different selective MEK inhibitors (U126, PD98059 and PD184352) on UM cell proliferation and apoptosis were studied. Results: The majority (30/44, 68.2%) of the primary UM tumors showed somatic mutation in codon 209 of either the GNAQ or the GNA11 genes. With the exception of one tumor, the mutations in either gene were mutually exclusive. Of the 30 UM primary tumors with GNAQ and/or GNA11 mutation, pERK1/2 expression was absent in 26.7%, weak in 33.3%, moderate in 23.3%, and high in only 16.7%. Western blot showed no pMEK1/2 expression in 6/14 (42.9%) of UM with either GNAQ or GNA11 mutations. Two of the UM cell lines with GNAQ mutation showed weak pERK1/2 expression. In addition one showed no pMEK1/2 expression while the other one showed very weak pMEK1/2 expression. Selective MEK inhibitors slowed UM cell proliferation but didn9t induce significant apoptosis in UM cell lines regardless of GNAQ status. Conclusions: Our results indicate that a significant number of UM with somatic mutations in GNAQ or GNA11 showed no MAPK pathway activation. In UM, MEK inhibition is mostly cytostatic suggesting that selective MEK inhibitors alone may not be sufficient to control UM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1127. doi:10.1158/1538-7445.AM2011-1127" @default.
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• W2332593577 date "2011-04-15" @default.
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• W2332593577 title "Abstract 1127: Lack of MAPK activation in significant number of uveal melanomas with somatic mutation inGNAQandGNA11" @default.
• W2332593577 doi "https://doi.org/10.1158/1538-7445.am2011-1127" @default.
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