Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer
Tóm tắt
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.
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Tài liệu tham khảo
Vander Heiden, 2009, Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science, 324, 1029, 10.1126/science.1160809
Koppenol, 2011, Otto Warburg's contributions to current concepts of cancer metabolism, Nat Rev Cancer, 11, 325, 10.1038/nrc3038
Wise, 2010, Glutamine addiction: a new therapeutic target in cancer, Trends Biochem Sci, 35, 427, 10.1016/j.tibs.2010.05.003
Hensley, 2013, Glutamine and cancer: cell biology, physiology, and clinical opportunities, J Clin Invest, 123, 3678, 10.1172/JCI69600
Gao, 2009, c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism, Nature, 458, 762, 10.1038/nature07823
Wang, 2010, Targeting mitochondrial glutaminase activity inhibits oncogenic transformation, Cancer Cell, 18, 207, 10.1016/j.ccr.2010.08.009
Seltzer, 2010, Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1, Cancer Res, 70, 8981, 10.1158/0008-5472.CAN-10-1666
Cheng, 2011, Pyruvate carboxylase is required for glutamine-independent growth of tumor cells, Proc Natl Acad Sci U S A, 108, 8674, 10.1073/pnas.1016627108
Le, 2012, Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells, Cell Metabolism, 15, 110, 10.1016/j.cmet.2011.12.009
van den Heuvel, 2012, Analysis of glutamine dependency in non-small cell lung cancer: GLS1 splice variant GAC is essential for cancer cell growth, Cancer Biol Ther, 13, 1185, 10.4161/cbt.21348
Yuneva, 2012, The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type, Cell Metab, 15, 157, 10.1016/j.cmet.2011.12.015
Son, 2013, Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway, Nature, 496, 101, 10.1038/nature12040
Gameiro, 2013, In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation, Cell Metab, 17, 372, 10.1016/j.cmet.2013.02.002
Timmerman, 2013, Glutamine sensitivity analysis identifies the xCT Antiporter as a common triple-negative breast tumor therapeutic target, Cancer Cell, 24, 450, 10.1016/j.ccr.2013.08.020
Cassago, 2012, Mitochondrial localization and structure-based phosphate activation mechanism of glutaminase C with implications for cancer metabolism, Proc Natl Acad Sci U S A, 109, 1092, 10.1073/pnas.1112495109
Kung, 2011, Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia, PLoS Genet, 7, e1002229, 10.1371/journal.pgen.1002229
Catane, 1979, Azaserine, DON, and azotomycin: three diazo analogs of L-glutamine with clinical antitumor activity, Cancer Treat Rep, 63, 1033
Robinson, 2007, Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), Biochem J, 406, 407, 10.1042/BJ20070039
Shukla, 2012, Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors, J Med Chem, 55, 10551, 10.1021/jm301191p
Kisner, 1980, The rediscovery of DON (6-diazo-5-oxo-L-norleucine), Recent Results Cancer Res, 74, 258, 10.1007/978-3-642-81488-4_30
Hartwick, 2012, BPTES inhibition of hGA(124–551), a truncated form of human kidney-type glutaminase, J Enzyme Inhib Med Chem, 27, 861, 10.3109/14756366.2011.622272
DeLaBarre, 2011, Full-length human glutaminase in complex with an allosteric inhibitor, Biochemistry, 50, 10764, 10.1021/bi201613d
Thangavelu, 2012, Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism, PNAS, 109, 7705, 10.1073/pnas.1116573109
Qie, 2014, ErbB2 activation upregulates glutaminase 1 expression which promotes breast cancer cell proliferation, J Cell Biochem, 115, 498, 10.1002/jcb.24684
Newcomb, 2002 17, Selective inhibition of glutaminase by bis-thiadiazoles
Li, 2013 10, Heterocyclic inhibitors of glutaminase
Neve, 2006, A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes, Cancer Cell, 10, 515, 10.1016/j.ccr.2006.10.008
Krebs, 1935, Metabolism of amino-acids: the synthesis of glutamine from glutamic acid and ammonia, and the enzymic hydrolysis of glutamine in animal tissues, Biochem J, 29, 1951, 10.1042/bj0291951
Curthoys, 1995, Regulation of glutaminase activity and glutamine metabolism, Annu Rev Nutr, 15, 133, 10.1146/annurev.nu.15.070195.001025
Bannai, 1986, Role of membrane transport in metabolism and function of glutathione in mammals, J Membr Biol, 89, 1, 10.1007/BF01870891
Cancer Genome Atlas Network, 2012, Comprehensive molecular portraits of human breast tumours, Nature, 490, 61, 10.1038/nature11412
Barretina, 2012, The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity, Nature, 483, 603, 10.1038/nature11003