谷氨酰胺酶抑制剂 CB-839 在三阴性乳腺癌中的抗肿瘤活性,Molecular Cancer Therapeutics

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谷氨酰胺酶抑制剂 CB-839 在三阴性乳腺癌中的抗肿瘤活性
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2014-02-12 , DOI: 10.1158/1535-7163.mct-13-0870
Matt I. Gross ₁ , Susan D. Demo ₁ , Jennifer B. Dennison ₁ , Lijing Chen ₁ , Tania Chernov-Rogan ₁ , Bindu Goyal ₁ , Julie R. Janes ₁ , Guy J. Laidig ₁ , Evan R. Lewis ₁ , Jim Li ₁ , Andrew L. MacKinnon ₁ , Francesco Parlati ₁ , Mirna L.M. Rodriguez ₁ , Peter J. Shwonek ₁ , Eric B. Sjogren ₁ , Timothy F. Stanton ₁ , Taotao Wang ₁ , Jinfu Yang ₁ , Frances Zhao ₁ , Mark K. Bennett ₁

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谷氨酰胺是许多肿瘤细胞的重要能量来源和积木。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 是两种谷氨酰胺酶剪接变体（KGA 和 GAC）的有效、选择性和口服生物可利用的抑制剂。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、谷氨酸生成、氧消耗以及谷胱甘肽和几种稳态水平的显着降低有关。三羧酸循环中间体。相比之下，在雌激素受体阳性细胞系 T47D 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，与受体阳性细胞相比，大多数 TNBC 细胞系的 GAC 蛋白表达和谷氨酰胺酶活性升高。此外，TNBC 亚型对 CB-839 治疗表现出最大的敏感性，这种敏感性与 (i) 依赖细胞外谷氨酰胺生长，(ii) 细胞内谷氨酸和谷氨酰胺水平，以及 (iii) GAC（但不是 KGA）表达相关，一种潜在的敏感性生物标志物。CB-839 在两种异种移植模型中显示出显着的抗肿瘤活性：作为单一药物用于患者来源的 TNBC 模型和基底样 HER2+ 细胞系模型 JIMT-1，作为单一药物和与紫杉醇联合使用。一起，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的临床研究提供了强有力的理由。摩尔癌症治疗; 13(4); 890-901。©2014 AACR。

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Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer

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, GAC protein 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+ 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. ©2014 AACR.

更新日期：2014-02-12

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