Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia

Willems, Lise; Jacque, Nathalie; Jacquel, Arnaud; Neveux, N.; Maciel, Thiago; Lambert, Mireille; Schmitt, Alain; Poulain, Laury; Green, Alexa S.; Uzunov, Madalina; Kosmider, Olivier; Radford‐Weiss, Isabelle; Moura, Ivan C.; Auberger, Patrick; Ifrah, Norbert; Bardet, Valérie; Chapuis, Nicolas; Lacombe, Catherine; Mayeux, Patrick; Tamburini, Jérôme; Bouscary, Didier

doi:10.1182/blood-2013-03-493163

Cited by 264 publications

(266 citation statements)

References 44 publications

Supporting

Mentioning

258

Contrasting

Unclassified

Order By: Relevance

“…The Cancer Genome Atlas (TCGA) pan-cancer gene expression data show high expression of GLS in acute myeloid leukemia, adrenocortical cancer, triple-negative breast cancer, colorectal cancer, kidney clear or papillary cell carcinoma, lung adenocarcinoma, melanoma, mesothelioma, pancreatic cancer, sarcoma and thyroid cancer [78,79]. Of these, GLS activity has been shown to be important for growth of acute myeloid leukemia [80][81][82], breast cancer [61,64,83,84], colorectal cancer [85], kidney cancer [86,87], lung cancer [88], melanoma [89,90] and pancreatic cancer cells [91] in studies that utilized smallmolecule inhibitors or gene-silencing approaches in cell lines. Further, glioblastoma cell lines have been found to be sensitive to glutaminase inhibitors in vitro, despite having relatively low GLS expression according to TCGA data [80,92].…”

Section: Kidney-type Glutaminase: Implications In Cancermentioning

confidence: 99%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

View full text Add to dashboard Cite

Many cancer cells exhibit an altered metabolic phenotype, in which glutamine consumption is upregulated relative to healthy cells. This metabolic reprogramming often depends upon mitochondrial glutaminase activity, which converts glutamine to glutamate, a key precursor for biosynthetic and bioenergetic processes. Two isozymes of glutaminase exist, a kidney-type (GLS) and a liver-type enzyme (GLS2 or LGA). While a majority of studies have focused on GLS, here we summarize key findings on both glutaminases, describing their structure and function, their roles in cancer and pharmacological approaches to inhibiting their activities.

show abstract

Section: Kidney-type Glutaminase: Implications In Cancermentioning

confidence: 99%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

View full text Add to dashboard Cite

show abstract

“…6 Recent studies have shown that L-asparaginase depletion of glutamine profoundly inhibits protein synthesis and produces a strong apoptotic response in primary AML cells. 30 Importantly, CD98 is the main heterodimerization partner for 6 amino acid transporters, which are dependent on the CD98 heavy chain for their localization and proper function. 23 Among those 6 transporters, the bi-directional transporters LAT-1 and LAT-2 export nonessential glutamine to enable the uptake of essential amino acids, which in turn activate the mammalian target of the rapamycin pathway promoting cell growth and survival.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of an anti‐CD98 antibody

et al. 2015

View full text Add to dashboard Cite

CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.CD98 is a heterodimeric protein that comprises a heavy and light chain. The CD98 heavy chain is a type II transmembrane glycoprotein that forms a heterodimer via covalent linkage to one of 6 amino acid transporters. 1,2 CD98 is overexpressed on the cell surface of almost all tumor cells, regardless of tissue origin and increased expression of a CD98-light chain, L-type amino acid transporter 1 (LAT-1) occurs in many types of human cancers, including breast, colon, oral, ovarian, esophageal, glioma and leukemia. 3,4 Increased uptake of amino acids supports the high growth rate of cancer cells by providing the building blocks for protein synthesis. [4][5][6] Moreover, the higher expression of CD98 heavy chain and LAT-1 in metastatic vs. primary tumors suggests that over-expression of CD98/LAT-1 may facilitate progression and metastasis of human cancers.CD98 also regulates integrin signaling by association with integrin b-subunits, thereby controlling cell proliferation, survival, migration, epithelial adhesion and polarity. 3,7 The function of CD98 in regulating both amino acid transport and integrin signaling can contribute to the rapid proliferation and clonal expansion of lymphocytes and tumor cells. 3 The expression pattern and pleiotropic function of CD98 heavy and light chains suggest these proteins are promising targets for treatment of a variety of human cancers. Although small molecule inhibitors of LAT-1 activity have demonstrated preclinical antitumor activity in a number of cancer cell types, including NSCLC, colon cancer, oral cancer and breast cancer, development of antibodies against CD98 heavy chain has received less focus. 5,[8][9][10] Murine monoclonal antibodies to CD98 inhibit lymphocyte proliferation and the growth of bladder cancer, lymphoma, glioma, prostate and colon cancer cells in preclinical models. [11][12][13] To identify therapeutic anti-CD98 antibodies with significant antitumor activity, we ...

show abstract

“…15 Antibodies against poly(ADP-ribose)polymerase (PARP), cleaved-CASPASE-3, CASPASE-8, p21, and p27 were obtained from Cell Signaling Technology (Beverly, MA); anti-b-ACTIN and anti-GLS2 (HPA038608) antibodies were from Sigma-Aldrich. Anti-GAC (19958-1-AP) and anti-GLS1 (20170-1-AP) antibodies were purchased from Proteintech (Manchester, United Kingdom).…”

Section: Western Blottingmentioning

confidence: 99%

“…13,14 We previously showed that targeting glutamine uptake can result in robust antileukemic responses in acute myeloid leukemia (AML), and we proposed the involvement of the mTORC1 signaling pathway downstream of glutamine addiction in this context. 15 However, little is known about mitochondrial metabolism in AML. Primary AML cells have an increased mitochondrial mass and oxygen consumption rate compared with normal hematopoietic cells, and targeting mitochondrial translation has antileukemic effects.…”

Section: Introductionmentioning

confidence: 99%

Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

Jacque

Ronchetti

Larrue

et al. 2015

Blood

Self Cite

341

277

View full text Add to dashboard Cite

• Genetic-or compound CB-839-induced GAC inhibition reduces OXPHOS and has antileukemic activity in AML.• GAC inhibition synergizes with BCL-2 inhibition by compound ABT-199.Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34 1 progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC K320A allele and the addition of the tricarboxyclic acid cycle product a-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML. (Blood. 2015;126(11):1346-1356

show abstract

Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia

Cited by 264 publications

References 44 publications

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

Antitumor activity of an anti‐CD98 antibody

Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

Contact Info

Product

Resources

About