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Abstract P3-02-09: Vulnerabilities in glutamine metabolism define triple-negative from Luminal A breast cancer subsets

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 hypothesised 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 radiolabelled and stable isotope tracing methods, we analysed in detail glutamine catabolism and its conversion into various metabolic products such as tricarboxylic acid (TCA) cycle intermediates, lipids, nucleotides, and amino acids in human breast cancer cell lines in vitro and ex vivo. These analyses revealed distinct metabolic effects across cell lines representing different subtypes of breast cancer, both at baseline and when glutamine uptake was blocked in vitro by L-gamma-glutamyl-p-nitroanilide (GPNA), a pharmacological inhibitor of ASCT2. These data confirm a broad reliance on glutamine availability in TN breast cancers, where glutamine anapleurosis was significantly greater than in the Luminal A subtype. Analysis of gene expression data from the METABRIC and TCGA patient datasets and the CCLE cell line dataset showed a specific upregulation of multiple glutamine metabolism enzymes in TN breast cancer patient samples and cell lines compared to the Luminal A subtype. These data suggest a rewiring of glutamine metabolism in TN breast cancer that utilises their addiction to glutamine to fuel cell growth. Furthermore, these data provide an additional suite of glutamine metabolic enzymes that may be therapeutically targeted in the hard-to-treat TN breast cancer subset. Citation Format: Michelle van Geldermalsen, Lake-Ee Quek, Nigel Turner, Seher Balaban, Andrew Hoy, Angel Pang, Yi Fang Guan, Kanu Wahi, Qian Wang, Jeff Holst. Vulnerabilities in glutamine metabolism define triple-negative from Luminal A breast cancer subsets [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-09.