Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer
Published version of a preprint
Abstract
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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Preclinical data combining CB-839 with traditional chemotherapies suggest improved efficacy over single agent administration.
“Preclinical data combining CB-839 with traditional chemotherapies have suggested improved efficacy over single agent administration [28]”
From Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer (2020) · cites this paper as [28]
Targeting glutaminase with chemical inhibitors decreases cancer cell proliferation in both in vitro and in vivo models.
“Mammals have two glutaminase genes, GLS and GLS2, and targeting the enzymes encoded by these genes with chemical inhibitors has been found to decrease cancer cell proliferation in both in vitro and in vivo models (Gross et al., 2014; Jacque et al., 2015; Le et al., 2012; Xiang et al., 2015; Yuneva et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Gross et al., 2014
CB-839, the first glutaminase inhibitor, has entered several clinical trials.
“Moreover, CB-839, the first glutaminase inhibitor, has entered several clinical trials14,15.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [14]
CB-839 is the only GLS inhibitor to proceed to clinical trials; its selectivity toward GLS1 and failure to inhibit GLS2 require in-depth study.
“Among these agents, CB-839 is the only one to proceed to clinical trials; however, its selectivity toward GLS1 and failure to inhibit the compensatory effect of GLS2 require in-depth study14.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [14]
CB-839 accumulated in orthotopic HOG cell tumors to levels comparable to those seen in orthotopic breast cancer xenografts.
“it accumulated in the orthotopic HOG cell tumors to levels comparable to those seen in orthotopic breast cancer xenografts”
From Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma (2018) · cites this paper as Gross et al., 2014
Expression of mutant IDH1 in NHA and HOG cells cooperated with CB-839 to deplete intracellular glutamate by more than 75% in vitro.
“expression of mutant IDH1 in NHA and HOG cells cooperated with the GLS inhibitor CB-839 (Gross et al., 2014) to deplete intracellular glutamate levels >75% in vitro”
From Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma (2018) · cites this paper as Gross et al., 2014
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- Authors
- Gross, M. I., Demo, S. D., Dennison, J. B., Chen, L., Chernov-Rogan, T., Goyal, B., Janes, J. R., Laidig, G. J., Lewis, E. R., Li, J., MacKinnon, A. L., Parlati, F., Rodriguez, M. L. M., Shwonek, P. J., Sjogren, E. B., Stanton, T. F., Wang, T., Yang, J., Zhao, F., & Bennett, M. K.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Bennett, Mark K.
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2014-04-01
- Volume
- 13
- Issue
- 4
- Pages
- 890-901
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2132117833
- Cited by
- 1,068
- References
- 31
- Citations by year
- 2026: 88 · 2025: 105 · 2024: 104 · 2023: 93 · 2022: 101 · 2021: 118 · 2020: 122 · 2019: 87 · 2018: 74 · 2017: 78 · 2016: 56 · 2015: 33 · 2014: 8
- FWCI
- 18.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- CB-839, glutaminase inhibitors, triple-negative breast cancer, glutamine metabolism, glutamate, glutathione, TCA cycle, GAC, cancer cell lines, xenograft models, paclitaxel combination therapy, biomarkers, targeted therapy
- MeSH terms
- Administration, Oral, Animals, Antineoplastic Agents, Dose-Response Relationship, Drug, Enzyme Inhibitors, Female, Glutaminase, Humans, Mammary Neoplasms, Experimental, Middle Aged, Sulfides, Thiadiazoles, Mice, SCID, Neoplasms, Basal Cell, Xenograft Model Antitumor Assays, Benzeneacetamides, Cell Line, Tumor, Mice, Triple Negative Breast Neoplasms
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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