Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

Hettmer, Simone; Schinzel, Anna C.; Tchessalova, Daria; Richards, Nigel G. J.; Hahn, William C.; Wagers, Amy J.

doi:10.1186/2194-7791-2-s1-a3

Cited by 22 publications

(53 citation statements)

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“…Nonetheless, and very importantly, ASNS inhibitor 1 (Fig. 1b) does negatively impact the growth of sarcoma cells in a manner similar to that seen when ASNS expression is reduced using siRNA knockdown methods 9 . Moreover, this compound is cytotoxic against asparaginase-resistant MOLT-4 leukemia cells when used at micromolar concentrations 21 .…”

mentioning

confidence: 58%

Molecular basis of human asparagine synthetase inhibitor specificity

Zhu

Radadiya

Bisson

et al. 2018

Preprint

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Expression of the enzyme human asparagine synthetase (ASNS) promotes metastatic progression in breast cancer, which affects L-asparagine levels and tumor cell invasiveness. Human ASNS has therefore emerged as a bona fide drug target for cancer therapy. We have reported a slow-onset, tight binding ASNS inhibitor with nanomolar affinity, but our compound exhibits poor cell permeability. On the other hand, we show here that this inhibitor exhibits remarkable selectivity for the human ASNS in HCT-116 cell lysates. By determining the first high-resolution (1.85 Å) X-ray crystal structure for human ASNS, we have built a computational model of the enzyme complexed to our inhibitor, which provides the first insights into the intermolecular interactions mediating specificity. These findings should facilitate the development of a second generation of ASNS inhibitors, leading to the discovery of drugs to prevent metastasis.Asparagine synthetase (ASNS) catalyzes the ATP-dependent biosynthesis of L-asparagine in cells from L-aspartic acid using L-glutamine as a nitrogen source 1 . L-asparagine is important for the growth and maintenance of acute lymphoblastic leukemias 2 , and breast 3 , lung 4 and castration-resistant prostate 5 cancers. Moreover, altering exogenous L-asparagine levels affects tumor cell invasiveness, and enforced expression of human ASNS promotes metastatic progression in breast cancer 6 , presumably by increasing the bioavailability of L-asparagine.Consistent with these findings, functional genomic screening of a murine sarcoma model, generated by oncogenic forms of Kras 7,8 , has demonstrated that silencing the gene encoding ASNS inhibits cell proliferation 9 . All of these observations strongly suggest that human ASNS is a bona fide drug target and that potent, small molecule ASNS inhibitors could have significant clinical utility in the prevention of metastasis 1 , and perhaps more broadly in cancer chemotherapy 10 .

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mentioning

confidence: 58%

Molecular basis of human asparagine synthetase inhibitor specificity

Zhu

Radadiya

Bisson

et al. 2018

Preprint

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“…The importance of asparagine for tumor growth is highlighted by the fact that depletion of asparagine pools with L-asparaginase inhibits translation elongation and is used in treating low-ASNS-expressing acute lymphoblastic leukemia and pediatric acute myeloid leukemia (Hill et al, 1967). Moreover, ASNS expression is required for the survival of cultured glioma and neuroblastoma cell lines (Zhang et al, 2014), as well as for the growth of mouse sarcomas (Hettmer et al, 2015). Asparagine levels were also shown to function in the regulation of amino-acid uptake, and to positively regulate the expression of genes of the serine synthesis pathway (Krall et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Translational and HIF11-Dependent Metabolic Reprograming Underpin Oncometabolome Plasticity and Synergy Between Oncogenic Kinase Inhibitors and Biguanides

et al. 2018

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“…Targeting of the molecular network that support sarcoma cell proliferation identified actionable gene targets encoding enzymes relevant to amino acid biosynthesis: asparagine synthetase (ASNS), branched chain aminotransferase 1 (BCAT1), phosphoserine aminotransferase (PSAT1) and phosphoglycerate dehydrogenase (PHGDH) 62 . Silencing of ASNS, an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic KRAS and disruption of Cdkn2A.…”

Section: Bioenergetic Properties and Metabolic Vulnerabilitiesmentioning

confidence: 99%

“…These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase, inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo, as well 62 . A recent report demonstrated that asparagine can suppress cell death in glutamine-deprived cells 63 , implicating asparagine in promoting cellular adaptation to metabolic stresses such as glutamine depletion.…”

Section: Bioenergetic Properties and Metabolic Vulnerabilitiesmentioning

confidence: 99%

Signaling pathways that overactivate metabolism and drive neoplasia, in rhabdomyosarcoma

Tselios¹,

Lambrou²

2019

JRPMS

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Inflammatory pathways that affect NF-kB, STAT3 and AP-1 are activated by tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation, and environmental stimuli, and in turn regulate expression of cytokines, adhesion molecules, proteases, anti-apoptotic factors, DNA repair factors, cell cycle and cell metabolism factors. NF-kB, STAT3 and AP-1 thereby control cell transformation, cell survival, proliferation, invasion, angiogenesis, metastasis, chemoresistance, and radioresistance of cancer. Deregulated activation of NF-kB, STAT3 and AP-1 family proteins is often associated with transition of cells from a differentiated phenotype to a stem cell-like unit, which may abnormally retain features of the differentiated cell. Common theme is the presence of features that are essential for the preservation of cell functions under unfavorable conditions related to stress,

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Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma

Cited by 22 publications

References 0 publications

Molecular basis of human asparagine synthetase inhibitor specificity

Molecular basis of human asparagine synthetase inhibitor specificity

Translational and HIF11-Dependent Metabolic Reprograming Underpin Oncometabolome Plasticity and Synergy Between Oncogenic Kinase Inhibitors and Biguanides

Signaling pathways that overactivate metabolism and drive neoplasia, in rhabdomyosarcoma

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