Targeting Glutamine Metabolism In Breast Cancer For Therapy

Metabolic reprogramming of cancer cells is observed in different types of tumors including breast. Oncogenic signals aid changes in metabolism that provide selective advantage to the cancer cells to meet their energy requirements to accomplish rapid proliferation. The increased dependence on the glycolytic pathway for energy called the “Warburg effect” was reported by Otto Warburg several decades ago. Our recent understanding of cancer metabolism has thrown light on alternative energy sources, especially glutamine and other branched chain amino acids. The role of glutamine in breast cancer cell growth has not yet been studied extensively. In this study we found that a number of breast cancer cell lines, especially those negative for ER, PR, HER2, display a high dependence on glutamine for their survival and growth. Interestingly, most of these glutamine-dependent cell lines express high levels of c-myc protein. Consistent with their growth dependency on glutamine, transaminases responsible for entry of glutamine into the tricarboxylic acid cycle are transcriptionally up regulated under low glutamine conditions. Consequently, growth of these cancer cell lines was found to be specifically inhibited by the transaminase inhibitor, amino oxyacetate (AOA). Moreover, the AOA mediated cytotoxic effect was partially c-myc dependent. Through 1H-NMR studies of AOA-treated cells we show that in addition to glutamine, AOA treatment decreases the aspartate and alanine content in the cells. In line with these findings, exogenous supplementation with aspartate partially rescued the cells from the growth inhibitory effects of AOA. Flow cytometry analysis showed that AOA causes cell cycle arrest in the S phase. AOA also had significant inhibitory effect on in vivo growth of rapidly growing SUM 149 and SUM159 xenografts in immunodeficient mice. When combined with chemotherapeutic agents, doxorubicin and carboplatin, AOA inhibited growth of MDA-MB-231 xenograft tumors more effectively than AOA alone. Lastly we present evidence that the cytotoxic effect of AOA is mediated through activation of the ER stress pathway, combined with depletion of key amino acids and likely, a reduction in the nucleoside pool in the cells. Our preclinical studies, both in vitro and in vivo, combined with development of intermediate markers of response, provide a strong rationale for testing AOA for therapy in Phase 0 clinical trials. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-01-01.