Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032.
Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032.
复制标题
DOI：
10.1186/1479-5876-8-39
复制
发表时间：
2010-04-20
影响因子：
7.4
通讯作者：
Ribas A
中科院分区：
文献类型：
--
作者：
Søndergaard JN;Nazarian R;Wang Q;Guo D;Hsueh T;Mok S;Sazegar H;MacConaill LE;Barretina JG;Kehoe SM;Attar N;von Euw E;Zuckerman JE;Chmielowski B;Comin-Anduix B;Koya RC;Mischel PS;Lo RS;Ribas A
阻断由BRAFV 600 E突变诱导的致癌信号传导是黑色素瘤治疗的一种有前途的方法。我们测试了Raf蛋白激酶的特异性抑制剂PLX 4032/RG 7204在黑色素瘤细胞系中的抗肿瘤作用。PLX 4032仅在具有BRAFV 600 E突变的细胞系中减少通过MAPK途径的信号传导。基于细胞活力测定，10个BRAFV 600 E突变体细胞系中有7个显示出敏感性，3个在高达10 μM的浓度下具有抗性。在敏感细胞系中，4个高度敏感，IC 50值低于1 μM，3个中度敏感，IC 50值在1 - 10 μM之间。在敏感和耐药细胞系中有MAPK通路抑制和细胞周期阻滞的证据。通过测序进行的基因组分析、通过质谱法对近400个致癌基因突变进行的基因分型以及SNP阵列表明，敏感细胞系和耐药细胞系之间在BRAF基因座扩增或其他致癌事件方面没有重大差异。然而，代谢示踪剂摄取研究表明，与耐药细胞系相比，敏感细胞系在暴露于PLX 4032后对FDG摄取具有更深刻的抑制作用。总之，BRAFV 600 E突变黑素瘤细胞系显示出对PLX 4032的一系列敏感性，并且使用PET探针的代谢成像可用于评估敏感性。
Blocking oncogenic signaling induced by the BRAFV600E mutation is a promising approach for melanoma treatment. We tested the anti-tumor effects of a specific inhibitor of Raf protein kinases, PLX4032/RG7204, in melanoma cell lines. PLX4032 decreased signaling through the MAPK pathway only in cell lines with the BRAFV600E mutation. Seven out of 10 BRAFV600E mutant cell lines displayed sensitivity based on cell viability assays and three were resistant at concentrations up to 10 μM. Among the sensitive cell lines, four were highly sensitive with IC50 values below 1 μM, and three were moderately sensitive with IC50 values between 1 and 10 μM. There was evidence of MAPK pathway inhibition and cell cycle arrest in both sensitive and resistant cell lines. Genomic analysis by sequencing, genotyping of close to 400 oncogeninc mutations by mass spectrometry, and SNP arrays demonstrated no major differences in BRAF locus amplification or in other oncogenic events between sensitive and resistant cell lines. However, metabolic tracer uptake studies demonstrated that sensitive cell lines had a more profound inhibition of FDG uptake upon exposure to PLX4032 than resistant cell lines. In conclusion, BRAFV600E mutant melanoma cell lines displayed a range of sensitivities to PLX4032 and metabolic imaging using PET probes can be used to assess sensitivity.
登录
查看更多内容
影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
4.8
作者：
Comín-Anduix, B;Boros, LG;Cascante, M
通讯作者：
Cascante, M
影响因子：
5.2
作者：
Sala, Elisa;Mologni, Luca;Gambacorti-Passerini, Carlo
通讯作者：
Gambacorti-Passerini, Carlo
影响因子：
4.4
作者：
Shu CJ;Radu CG;Shelly SM;Vo DD;Prins R;Ribas A;Phelps ME;Witte ON
通讯作者：
Witte ON
DOI：
10.1073/pnas.0711741105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Tsai, James;Lee, John T.;Bollag, Gideon
通讯作者：
Bollag, Gideon