Regulation of arginine metabolism as a therapeutic target in breast cancer

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Abstract Cancer cells contain alterations that promote cell growth and survival. One such alteration is aberrant activation of oncogenic signaling pathways. The PI3K/Akt/mTORC1 pathway is altered in nearly 70% of breast cancers, and thus multiple targeted therapies have been developed for use in breast cancers with pathway alterations. However, clinical efficacy has been disappointing, with limited activity from single agents. Additionally, many breast cancers do not contain a single driver mutation, and targeted therapies are unlikely to eliminate all breast cancer cells due to tumor heterogeneity. Interest in studying the relationship between cancer and metabolism has arisen as an avenue to identify novel biomarkers and therapeutic targets that are effective across multiple breast cancer subtypes. These metabolic changes allow cells to survive in the tumor microenvironment. The nonessential amino acid arginine is a candidate for metabolic therapy because it can become essential in cancer cells. Arginine starvation therapy has been effective in arginine auxotrophic cancers, such as malignant melanoma and hepatocellular carcinoma. However, preliminary data suggest that breast cancer cells vary in their sensitivity to arginine starvation, and it is not yet known what determines this varied sensitivity. Our studies also described correlations between resistance to PI3K and Akt inhibitors and alterations in arginine metabolism, indicating that PI3K/Akt/mTORC1 signaling may be related to the regulation of arginine metabolism in breast cancer. I hypothesize that the different requirements for arginine-derived metabolites across breast cancer cell lines can be exploited to inhibit breast cancer cell growth and survival. The goal of this proposal is to determine how arginine availability leads to changes in arginine metabolism, and how these changes can be targeted to decrease breast cancer cell viability in specific cellular settings. I first aim to classify breast cancer cell lines by their responses to arginine, and identify differences between these cells lines that can be used as novel therapeutic targets or biomarkers for sensitivity to arginine starvation therapy. In my second aim, I will investigate the role of mTORC1 signaling as an arginine sensor to determine its ability to regulate arginine metabolism. Finally, I will investigate arginine metabolic therapy in the context of breast cancer cells that are resistant to PI3K/Akt inhibitors. Determining variations that account for different responses to arginine, including mTORC1-dependent responses, will broaden our knowledge of metabolic regulation. It will also identify novel therapeutic targets and biomarkers for response to arginine metabolic therapy in breast cancer, increasing our ability to combat this disease, including in drug-resistant settings. As a whole, this project will expand our knowledge of the role of arginine metabolism in breast cancer and its value in therapy.