Abstract B20: Glutamine metabolic vulnerabilities define triple-negative from luminal A breast cancer subsets

Abstract

Abstract Although a nonessential amino acid in normal cells, the demand for glutamine is dramatically increased throughout malignant transformation to support increased metabolic demands; namely, provision of catabolic substrates for ATP production and anabolic substrates for the citric acid cycle and subsequent macromolecule biosynthesis, as well as potentiating the uptake of other critical amino acids by acting as an obligate exchange substrate. Elevated expression of glutamine metabolism-related genes, MYC-driven transcriptional events, and increased consumption and reliance on glutamine are all associated with aggressive breast cancers, including the high-risk triple-negative (TN) subtype. We recently showed that in breast cancer cells, glutamine uptake by the small neutral amino acid transporter, ASCT2, is required to sustain TN cell growth in vitro and in vivo. We therefore hypothesized that highly proliferative TN breast cancers that are sensitive to ASCT2 inhibition may have unique metabolic signatures that could be additionally exploited for therapeutic purposes. Using a targeted metabolomics approach, we combined labeled substrate tracing, liquid chromatography coupled tandem-mass spectrometry (LC-MS/MS), and gas chromatography mass spectrometry (GC-MS) to analyze intracellular levels of key tricarboxylic acid (TCA) cycle intermediates, glycolytic metabolites, fatty acid precursors, and amino acids in human breast cancer cell lines. These analyses revealed distinct metabolic effects when glutamine uptake was blocked in vitro by L-γ-glutamyl-p-nitroanilide (GPNA), a pharmacologic inhibitor of ASCT2. These data confirm a broad reliance on glutamine availability in TN breast cancers, reinforced by TCGA gene expression data showing a specific upregulation of multiple glutamine metabolism enzymes that is completely absent in the luminal A subtype. These data emphasize the link between increased glutamine metabolism and clinically aggressive breast cancers, thus highlighting the therapeutic potential of targeting glutamine metabolism pathways in these patients. Citation Format: Michelle van Geldermalsen, Lake-Ee Quek, Nigel Turner, Seher Balaban, Andrew Hoy, Qian Wang, Jeff Holst. Glutamine metabolic vulnerabilities define triple-negative from luminal A breast cancer subsets [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B20.