Targeted inhibition of glutaminase as a potential new approach for the treatment of associated soft tissue malignancies.

Many cancer cells rely on glutamine as the source of carbon molecules to feed the biosynthetic pathways and are often addicted to glutaminolysis. Inhibitors of glutaminase activity have gained attention in the last few years due to their anti-proliferative effect and ability to induce apoptosis in some cancers. Although it is a promising therapeutic approach, its efficacy or the role played by glutamine in modulating cell proliferation in associated tumors has never been studied. We report for the first time, a strong correlation between the status of tumor cells and increased sensitivity to glutamine deprivation and glutaminase inhibition. Soft-tissue cell lines null for were highly dependent on glutamine for proliferation and showed decreased mTORC1 and Ras activity in response to glutaminase inhibition. Re-addition of glutamine or intermediary metabolite such as glutamate to the media restored mTORC1 and Ras activity. SiRNA mediated knockdown in wild-type cell line shows increased sensitivity to glutaminase inhibition. Conversely, overexpression in null cell lines results in reduced sensitivity to glutaminase inhibition, and restores mTORC1 signaling and Ras activity. These findings provide new insights into the role played by glutamine metabolism in associated tumors and strongly warrant further investigation as a potential therapy in the disease setting.