Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer
Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer
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DOI：
10.1158/1535-7163.mct-13-0870
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发表时间：
2014-04-01
影响因子：
5.7
通讯作者：
Bennett, Mark K.
中科院分区：
文献类型：
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作者：
Gross, Matt I.;Demo, Susan D.;Bennett, Mark K.
谷氨酰胺是许多肿瘤细胞的重要能量来源和构建模块。谷氨酰胺利用的第一步是通过线粒体酶谷氨酰胺酶将其转化为谷氨酸。CB-839是一种强效的、选择性的、口服生物可利用的辅酶A酶剪接变体（KGA和GAC）抑制剂。CB-839在三阴性乳腺癌（TNBC）细胞系HCC-1806中具有抗增殖活性，这与谷氨酰胺消耗、谷氨酸产生、耗氧量以及谷胱甘肽和几种三羧酸循环中间体的稳态水平显著降低相关。相反，在雌激素受体阳性细胞系T47 D中未观察到抗增殖活性，并且仅观察到对谷氨酰胺消耗和下游代谢物的适度影响。在一组乳腺癌细胞系中，相对于受体阳性细胞，大多数TNBC细胞系中的GAC蛋白表达和转氨酶活性升高。此外，TNBC亚型显示出对CB-839治疗的最大敏感性，并且该敏感性与（i）生长对细胞外谷氨酰胺的依赖性，（ii）细胞内谷氨酸和谷氨酰胺水平，和（iii）GAC（而非KGA）表达（敏感性的潜在生物标志物）相关。CB-839在两种异种移植模型中显示出显著的抗肿瘤活性：在患者来源的TNBC模型中作为单一药剂，以及在基底样HER 2（匕首）细胞系模型JIMT-1中作为单一药剂和与紫杉醇组合。总之，这些数据为CB-839作为TNBC和其他谷氨酰胺依赖性肿瘤患者的靶向治疗药物的临床研究提供了强有力的依据。Mol Cancer Ther; 13（4）; 890-901.（C）2014年AACR。
Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor-positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GACprotein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2(dagger) cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors. Mol Cancer Ther; 13(4); 890-901. (C)2014 AACR.