Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy

Genetic and microenvironmental factors can 'lock' tumor cells into a state of glutamine addiction and dependence on glutaminase (GLS). Oxidative stress and activation of the NRF2-antioxidant response pathway are conserved biomarkers for tumor sensitivity to GLS inhibitors. Glutamine antagonism reconditions the tumor microenvironment and can enhance the anticancer immune response through both direct and indirect mechanisms. Clinical trial results to date have shown tolerability of the GLS inhibitor CB-839, but mixed results with regard to efficacy, indicating the need to continue mechanistic, pharmacological, and translational research. Targeting conserved biomarkers and developing rational drug synergisms will enhance the efficacy of glutamine metabolism inhibitors in cancer therapy. Glutamine metabolism is reprogrammed during tumorigenesis and has been investigated as a promising target for cancer therapy. However, efforts to drug this process are confounded by the intrinsic metabolic heterogeneity and flexibility of tumors, as well as the risk of adverse effects on the anticancer immune response. Recent research has yielded important insights into the mechanisms that determine the tumor and the host immune responses to pharmacological perturbation of glutamine metabolism. Here, we discuss these findings and suggest that, collectively, they point toward patient stratification and drug combination strategies to maximize the efficacy of glutamine metabolism inhibitors as cancer therapeutics. Glutamine metabolism is reprogrammed during tumorigenesis and has been investigated as a promising target for cancer therapy. However, efforts to drug this process are confounded by the intrinsic metabolic heterogeneity and flexibility of tumors, as well as the risk of adverse effects on the anticancer immune response. Recent research has yielded important insights into the mechanisms that determine the tumor and the host immune responses to pharmacological perturbation of glutamine metabolism. Here, we discuss these findings and suggest that, collectively, they point toward patient stratification and drug combination strategies to maximize the efficacy of glutamine metabolism inhibitors as cancer therapeutics. the process of replenishing the intermediates of a metabolic pathway. In proliferating cells, the TCA cycle serves as a source of biosynthetic precursors and thereby loses carbon (cataplerosis). To maintain metabolic homeostasis, anaplerotic flux must match cataplerotic flux. innate and adaptive immune responses that contribute to the control of tumor growth. The immune system interacts with cancer cells in three phases – elimination, equilibrium, and escape. In the elimination phase, the immune system destroys cancer cells, and in the equilibrium phase the tumor remains stable. In the escape phase, cancer cells evade the immune system and an immunosuppressive environment is established. Cancer immunotherapy approaches aim to restore immune control of cancer. a molecule that is chemically similar to a natural metabolite, but which inhibits the normal processing of that metabolite. Antimetabolites can interfere with the functions of one or more of the enzymes that normally interact with the natural metabolite, thereby affecting the cell's normal metabolic processes. an amidohydrolase enzyme that catalyzes the conversion of glutamine to glutamate and an ammonium ion. a cellular mechanism that coordinates the response to oxidative and electrophilic stress by upregulating the transcription factor NRF2. The transcriptional targets of NRF2 include genes encoding key mediators of the detoxification and elimination of reactive oxidants and electrophiles. NRF2 is negatively regulated by KEAP1, a tumor suppressor whose function is frequently lost in NSCLC. tumors comprise a heterogeneous population of cancer cells and also contain both resident and infiltrating host cells, such as CAFs, endothelial cells, and lymphocytes. Together with the ECM, the tumor interstitial fluid, and secreted factors, these components constitute the TME. the gene product SLC7A11 (xCT) heterodimerizes with SLC3A2 to form the plasma membrane cystine/glutamate antiporter (system xc−), which plays a role in the antioxidant response by supplying cysteine, the rate-limiting substrate for glutathione biosynthesis. The SLC7A11 gene is a transcriptional target of NRF2.