Advancing Cancer Treatment by Targeting Glutamine Metabolism—A Roadmap

SIMPLE SUMMARY: Dysregulated glutamine metabolism is one of the metabolic features evident in cancer cells when compared to normal cells. Cancer cells utilize glutamine for energy generation as well as the synthesis of other molecules that are critical for cancer growth and progression. Therefore, drugs targeting glutamine metabolism have been extensively investigated. However, inhibition of glutamine metabolism in cancer cells results in the activation of other metabolic pathways enabling cancer cells to survive. In this review, we summarize and discuss the targets in glutamine metabolism, which has been probed in the development of anticancer drugs in preclinical and clinical studies. We further discuss pathways activated in response to glutamine metabolism inhibition, enabling cancer cells to survive the challenge. Finally, we put into perspective combined treatment strategies targeting glutamine metabolism along with other pathways as potential treatment options. ABSTRACT: Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.