Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis

Xiang, Yan; Stine, Zachary E.; Xia, Jinsong; Lu, Yunqi; O’Connor, Roddy S.; Altman, Brian J.; Hsieh, Annie L.; Gouw, Arvin M.; Thomas, Ajit G.; Gao, Ping; Sun, Linchong; Song, Libing; Yan, Benedict; Slusher, Barbara S.; Zhuo, Jingli; Ooi, London Lucien; Lee, Caroline; Mancuso, Anthony A.; McCallion, Andrew S.; Le, Anne; Milone, Michael C.; Rayport, Stephen; Felsher, Dean W.; Dang, Chi V.

doi:10.1172/jci75836

Cited by 332 publications

(294 citation statements)

References 61 publications

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“…In fact, glutamine metabolism is increased in T-cell activation and regulates skewing of CD4 + Tcells towards more inflammatory subtypes 32, 185,186 . While ex vivo experiments suggest that lymphocytes show signs of proper activation even in the presence of CB-839 173 , it remains to be seen how GLS inhibition will affect anti-tumor immunity in vivo. Studies in mouse lymphocytes suggest that the CB-839-insensitive GLS2 may play a key role in lymphocyte proliferation 144 , and so targeting of glutamine metabolism through the modulation of tumor-specific pathways may be required to maintain both high glutamine availability and immune response.…”

Section: Metabolic Synthetic Lethality and Combination Therapymentioning

confidence: 99%

“…While most of these are still in the preclinical 'tool compound' stage or have been limited by toxicity, allosteric inhibitors of GLS have shown promise in preclinical models of cancer, and one highly potent compound in this class, CB-839, has moved on to clinical trials. A preclinical tool-compound inhibitor of GLS is bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) 172 , which has been shown to block the growth of cancer cells in vitro, of xenografts in vivo, and to slow tumor growth and prolong survival in genetically engineered mouse models of cancer 151,173 . CB-839 has shown efficacy against triple negative breast cancer and hematological malignancies in preclinical studies 53,54 , and is currently the subject of several clinical trials.…”

Section: Therapymentioning

confidence: 99%

“…Nevertheless, glutamine metabolism has been documented as critical for tumorigenesis and tumor survival in specific in vivo models 151,173,192,193 , which have varied metabolic profiles depending on the tumor oncogenotype. The complexities in vivo are exemplified by a study utilizing mouse models to compare the effects of metabolic driver and tissue of origin on tumor metabolism 177 ( Figure 8).…”

Section: Glutamine Usage: Plastic Versus Patientmentioning

confidence: 99%

“…Likewise, MYC-driven lung tumors upregulated both GLS and glutamine synthetase, consistent with a recent study showing that MYC indirectly induces glutamine synthetase 177,178 . Conversely, MYC-driven liver tumors upregulated GLS and SLC1A5 and avidly consumed and catabolized glutamine 173,177 ( Figure 8). In fact, in this same MYC-driven liver cancer model, loss of a single copy of GLS slowed tumor growth and pharmacologic inhibition of GLS prolonged survival 173 ,…”

Section: Glutamine Usage: Plastic Versus Patientmentioning

confidence: 99%

“…Conversely, MYC-driven liver tumors upregulated GLS and SLC1A5 and avidly consumed and catabolized glutamine 173,177 ( Figure 8). In fact, in this same MYC-driven liver cancer model, loss of a single copy of GLS slowed tumor growth and pharmacologic inhibition of GLS prolonged survival 173 ,…”

Section: Glutamine Usage: Plastic Versus Patientmentioning

confidence: 99%

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Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

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222

108

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The resurgence of research in cancer metabolism has recently broadened interests beyond glucose and the Warburg Effect to other nutrients including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

show abstract

Section: Metabolic Synthetic Lethality and Combination Therapymentioning

confidence: 99%

Section: Therapymentioning

confidence: 99%

Section: Glutamine Usage: Plastic Versus Patientmentioning

confidence: 99%

Section: Glutamine Usage: Plastic Versus Patientmentioning

confidence: 99%

Section: Glutamine Usage: Plastic Versus Patientmentioning

confidence: 99%

See 3 more Smart Citations

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

Self Cite

222

108

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show abstract

HRD1 inhibits fatty acid oxidation and tumorigenesis by ubiquitinating CPT2 in triple‐negative breast cancer

Guo

Wang

et al. 2020

Molecular Oncology

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In the current study, we demonstrated that HRD1 was downregulated in TNBC tissues and dysregulated FAO by ubiquitinating CPT2, especially under glutamine‐deficient conditions. In addition, the curative effect of CB839 is more prominent in TNBC cells and tumors with high HRD1 expression. These findings provide insight into HRD1 as a regulator of lipid metabolism and have important implications for TNBC therapeutic targeting.

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The critical function of metabolic reprogramming in cancer metastasis

Xie

Pan

et al. 2022

Aging and Cancer

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Cancer metastasis is the leading cause of cancer‐related death. It is a complex, inefficient, and multistep process related to poor prognosis and high mortality of patients. Increasing evidence has shown that metabolic programming is a recognized hallmarker of cancer, plays a critical role in cancer metastasis. Metabolism alterations of glucose, lipid, and amino acid provide cancer cells with energy and substances for biosynthesis, maintain biofunctions and significantly affect proliferation, invasion, and metastasis of cancer cells. Tumor microenvironment (TME) is a complex system formed by varieties of cellular and noncellular elements. Nontumor cells in TME also undergo metabolic reprogramming or respond to metabolites to promote migration and invasion of cancer cells. A comprehensive understanding of the regulatory mechanism in metastasis from the metabolic reprogramming aspect is required to develop new therapeutic strategies combatting cancer metastasis. This review illustrates the metabolic reprogramming and interaction of cancer cells and nontumor cells in the TME, and the development of treatment strategies targeting metabolism alterations.

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Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis

Cited by 332 publications

References 61 publications

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

HRD1 inhibits fatty acid oxidation and tumorigenesis by ubiquitinating CPT2 in triple‐negative breast cancer

The critical function of metabolic reprogramming in cancer metastasis

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