Glutamine Sensitivity Analysis Identifies the xCT Antiporter as a Common Triple-Negative Breast Tumor Therapeutic Target.

UCSF/Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA. Electronic address: .
Cancer cell (Impact Factor: 25.29). 10/2013; DOI: 10.1016/j.ccr.2013.08.020
Source: PubMed

ABSTRACT A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on one-third of triple-negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory sulfasalazine decreases tumor growth, revealing a therapeutic target in breast tumors of poorest prognosis and a lead compound for rapid, effective drug development.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The function of a cysteine-glutamate exchanger (xCT) transporter is to increase the intracellular concentration of glutathione in order to protect cells from oxidative stress. In several types of cancer, xCT is thought to play a role in the onset of resistance to chemotherapy and radiotherapy. xCT is stabilized on the tumor cell surface after combining with cluster of differentiation 44 variant (CD44v). We examined the xCT and CD44v6 expression in 304 primary tumor samples obtained from patients with colorectal cancer using immunohistochemical analysis. Immunoreactivity for xCT was observed in 208 (68.4%) tumors. Among 218 patients with stage I-III disease who underwent curative surgery, the postoperative recurrence rate was 32.9% in those with xCT-positive tumors, which was significantly (p=0.003) higher than in those with xCT-negative tumors (10.7%). Immunoreactivity for CD44v6 was observed in 101 cases (33.2%), although the rate of postoperative recurrence in patients with CD44v6-positive tumors did not exhibit any significant correlation. Multivariate analyses revealed increased xCT expression to be an independent significant predictor of disease recurrence, in addition to depth of tumor invasion, lymph node metastasis and venous invasion. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
    Anticancer research 02/2015; 35(2):677-82. · 1.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent work has highlighted glutaminase (GLS) as a key player in cancer cell metabolism, providing glutamine-derived carbon and nitrogen to pathways that support proliferation. There is significant interest in targeting GLS for cancer therapy, although the gene is not known to be mutated or amplified in tumors. As a result, identification of tractable markers that predict GLS dependence is needed for translation of GLS inhibitors to the clinic. Herein we validate a small molecule inhibitor of GLS and show that non-small cell lung cancer cells marked by low E-cadherin and high vimentin expression, hallmarks of a mesenchymal phenotype, are particularly sensitive to inhibition of the enzyme. Furthermore, lung cancer cells induced to undergo epithelial to mesenchymal transition (EMT) acquire sensitivity to the GLS inhibitor. Metabolic studies suggest that the mesenchymal cells have a reduced capacity for oxidative phosphorylation and increased susceptibility to oxidative stress, rendering them unable to cope with the perturbations induced by GLS inhibition. These findings elucidate selective metabolic dependencies of mesenchymal lung cancer cells and suggest novel pathways as potential targets in this aggressive cancer type.
    PLoS ONE 12/2014; 9(12):e115144. DOI:10.1371/journal.pone.0115144 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The tumor suppressors Pten and p53 are frequently lost in breast cancer, yet the consequences of their combined inactivation are poorly understood. Here, we show that mammary-specific deletion of Pten via WAP-Cre, which targets alveolar progenitors, induced tumors with shortened latency compared to those induced by MMTV-Cre, which targets basal/luminal progenitors. Combined Pten-p53 mutations accelerated formation of claudin-low, triple-negative-like breast cancer (TNBC) that exhibited hyper-activated AKT signaling and more mesenchymal features relative to Pten or p53 single-mutant tumors. Twenty-four genes that were significantly and differentially expressed between WAP-Cre:Pten/p53 and MMTV-Cre:Pten/p53 tumors predicted poor survival for claudin-low patients. Kinome screens identified eukaryotic elongation factor-2 kinase (eEF2K) inhibitors as more potent than PI3K/AKT/mTOR inhibitors on both mouse and human Pten/p53-deficient TNBC cells. Sensitivity to eEF2K inhibition correlated with AKT pathway activity. eEF2K monotherapy suppressed growth of Pten/p53-deficient TNBC xenografts in vivo and cooperated with doxorubicin to efficiently kill tumor cells in vitro. Our results identify a prognostic signature for claudin-low patients and provide a rationale for using eEF2K inhibitors for treatment of TNBC with elevated AKT signaling.
    EMBO Molecular Medicine 10/2014; 6(12):1542-1560. DOI:10.15252/emmm.201404402 · 8.25 Impact Factor


Available from
May 28, 2014