Ikediobi Ogechi N, Reimers Mark, Durinck Steffen, Blower Paul E, Futreal Andrew P, Stratton Michael R, Weinstein John N
Genomics and Bioinformatics Group, Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland, USA.
Mol Cancer Ther. 2008 Jun;7(6):1337-46. doi: 10.1158/1535-7163.MCT-07-2308. Epub 2008 Jun 4.
The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. We previously sequenced 24 cancer genes in those cell lines. Eleven of the genes were found to be mutated in three or more of the lines. Using a pharmacogenomic approach, we analyzed the relationship between drug activity and mutations in those 11 genes (APC, RB1, KRAS, NRAS, BRAF, PIK3CA, PTEN, STK11, MADH4, TP53, and CDKN2A). That analysis identified an association between mutation in BRAF and the antiproliferative potential of phenothiazine compounds. Phenothiazines have been used as antipsychotics and as adjunct antiemetics during cancer chemotherapy and more recently have been reported to have anticancer properties. However, to date, the anticancer mechanism of action of phenothiazines has not been elucidated. To follow up on the initial pharmacologic observations in the NCI-60 screen, we did pharmacologic experiments on 11 of the NCI-60 cell lines and, prospectively, on an additional 24 lines. The studies provide evidence that BRAF mutation (codon 600) in melanoma as opposed to RAS mutation is predictive of an increase in sensitivity to phenothiazines as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay (Wilcoxon P = 0.007). That pattern of increased sensitivity to phenothiazines based on the presence of codon 600 BRAF mutation may be unique to melanomas, as we do not observe it in a panel of colorectal cancers. The findings reported here have potential implications for the use of phenothiazines in the treatment of V600E BRAF mutant melanoma.
美国国立癌症研究所为抗癌药物研发而收集的60种人类癌细胞系（NCI - 60）是一种广泛使用的资源。我们之前对这些细胞系中的24个癌症基因进行了测序。发现其中11个基因在三个或更多细胞系中发生了突变。我们采用药物基因组学方法，分析了这11个基因（APC、RB1、KRAS、NRAS、BRAF、PIK3CA、PTEN、STK11、MADH4、TP53和CDKN2A）的突变与药物活性之间的关系。该分析确定了BRAF突变与吩噻嗪类化合物的抗增殖潜力之间存在关联。吩噻嗪类药物已被用作抗精神病药物以及癌症化疗期间的辅助止吐药，最近有报道称其具有抗癌特性。然而，迄今为止，吩噻嗪类药物的抗癌作用机制尚未阐明。为了跟进NCI - 60筛选中的初步药理学观察结果，我们对11种NCI - 60细胞系进行了药理学实验，并前瞻性地对另外24种细胞系进行了实验。这些研究提供了证据，表明与RAS突变相反，黑色素瘤中的BRAF突变（密码子600）可预测对吩噻嗪类药物的敏感性增加，这是通过3 -（4,5 - 二甲基噻唑 - 2 - 基）- 5 -（3 - 羧甲氧基苯基）- 2 -（4 - 磺基苯基）- 2H - 四唑鎓内盐测定法确定的（Wilcoxon P = 0.007）。基于密码子600 BRAF突变而对吩噻嗪类药物敏感性增加的这种模式可能是黑色素瘤所特有的，因为我们在一组结直肠癌中未观察到这种情况。本文报道的研究结果对吩噻嗪类药物用于治疗V600E BRAF突变型黑色素瘤具有潜在意义。
