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The tyrosine kinase functionality of these enzymes is typic


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СообщениеДобавлено: 07:06 20-11-2015    Заголовок сообщения: The tyrosine kinase functionality of these enzymes is typic Ответить с цитатой

Among the BRAFV600E mutant cutaneous group we chose M229 and M249 as representatives of highly sensitive cutaneous cell lines, and M233 and M263 as resistant cutaneous cell lines. AP24534 VEGFR 阻害剤 In our panel, all the uveal melanoma cell lines were sensitive to TAK733 and we picked three as representative samples with GNAQ mutations. As expected based on prior data, MEK inhibition resulted in increase of pMEK in non BRAFV600E mutant cell lines. This was more prominent in NRASQ61L mutant and uveal melanoma cell lines than in BRAFV600E mutant cell lines, which had a higher baseline level of pMEK. In all cases, TAK733 induced a marked dose dependent decrease of pERK, regardless of the driver oncogenic mutation or the sensitivity or resistance to this agent in cell viability assays.<br><br> On the contrary, effects on pAKT and pS6K AT-406 dissolve 溶解度 var ied according to the cell origin, oncogenic events and sensitivity to TAK733. BRAFV600E mutant cell lines re sistant to TAK733 showed no inhibition of pAKT or pS6K, while there was a general trend towards inhibition of these two phosphorylated molecules in sensitive cell lines. Of note, in the uveal melanoma cell lines and in the cutaneous melanoma cell line M229, the baseline level of pAKT was undetectable by Western blot, so no inhibition could be recorded in them. Changes in pS6 tended to follow changes in pS6K in the cutaneous melanoma cell lines but not in the uveal melanoma cell lines. In a time course analysis of signaling events upon exposure to TAK733, both the sensitive M229 and the resistant M233 cell lines with BRAFV600E mutations showed initial inhib ition of pERK, but the resistant cell line recovered pERK signaling with time.<br><br> This different time course effect was not evident for the in hibition of pAKT or pS6K in the resistant cell line, while they were permanently inhibited over the 48 hour study period in the sensitive cell line. Differential metabolic akt2 阻害剤 tracer uptake between cell lines sensitive and resistant to TAK733 We explored the use of metabolic tracers to differentiate response or resistance to TAK733 in six cutaneous mel anoma cell lines with the goal of a future use of these tracers in PET scanning studies in the clinic. Thymidine is taken up by proliferating cells and the PET tracer FLT can be used in patients. Consistent with the cell cycle analysis data, all the tested cell lines had some degree of inhibition of tritium labeled thymidine uptake upon exposure to TAK733 regardless of their sensitivity in vitro.<br><br> The highest levels of inhibition were in the highly sensitive BRAFV600E mutant cell lines M229 and M249 and the relatively resistant M263 cell line. Changes in uptake of tritium labeled 2 deoxy D glucose were analyzed to study effects of TAK733 on PET scans with the commonly used PET tracer FDG. The lowest degree of inhibition was in the two most resistant cell lines, the BRAFV600E mutant M233 and the NRASQ61K mutant M244. Therefore, changes in the uptake of the 3H 2DDG metabolic tracer most closely followed the results of the cell viability assays. Discussion Initial data testing MEK inhibitors in melanoma cell lines suggested a high level and selective sensitivity in BRAFV600E mutant melanoma cell lines, with low sensi tivity in melanoma cell lines with other driver onco genes.
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