Abstract 3584: Effects of the investigational selective MEK inhibitor TAK-733 against cutaneous and uveal melanoma cell lines
| Autor: | Tara A. McCannel, David I. Lichter, Mohammad Atefi, Sybil Zachariah, Antoni Ribas, Barry L. Burgess, Narsis Attar, Erika von Euw, Elena S. Izmailova |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Cancer Research. 71:3584-3584 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2011-3584 |
| Popis: | Background. There are several MEK inhibitors currently under clinical investigation, including, TAK-733, a novel non-ATP-competitive allosteric selective inhibitor of MEK. We have analyzed the sensitivity of human melanoma cell lines of different origins to TAK-733. Methods. The half maximal inhibitory concentration (IC50) of TAK-733 was assessed in a panel of 27 skin melanoma cell lines and 5 ocular melanoma cell lines genotyped for driver and secondary oncogenic mutations. Flow cytometry was used to analyze effects on cell cycle progression, and Western blots to analyze the downstream signaling changes upon exposure to TAK-733. Results. Among 12 BRAFV600E mutated cell lines tested, 6 were sensitive to TAK-733 with IC50s less than 10 nM, including 4 highly sensitive cell lines with IC50s below 1 nM. In 5 cell lines with BRAFV600E mutation the IC50 was higher than 100 nM and were considered highly resistant. Among 10 NRASQ61L mutant melanoma cell lines, 6 were sensitive with IC50s below 10 nM. Among 5 melanoma cell lines with wild type sequences for NRAS, BRAF, GNAQ and GNA11 genes only 1 was sensitive to TAK-733. All 5 of the uveal melanoma cell lines were highly sensitive to TAK-733 IC50 regardless of having a GNAQ or GNA11 mutations. MEK inhibition resulted in increase of pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. In all cases TAK-733 induced marked dose-dependent inhibition of pERK, regardless of the driver oncogenic mutation or the sensitivity or resistance to this agent in cell viability assays. Cell lines resistant to TAK-733 showed no inhibition of pAKT or pS6K, while there was a general trend towards inhibition of these two phosphorylated molecules in sensitive cell lines. Conclusions. TAK-733 is a potent MEK inhibitor with high antitumor activity against human melanoma cell lines with BRAF, NRAS, GNAQ and GNA11 driver mutations. 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 3584. doi:10.1158/1538-7445.AM2011-3584 |
| Databáze: | OpenAIRE |
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