Advancing Cancer Treatment by Targeting Glutamine Metabolism—A Roadmap

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.

mTORC1-Inhibition Potentiating Metabolic Block by Tyrosine Kinase Inhibitor Ponatinib in Multiple Myeloma

“…To enable this, the cancer cells accumulate plasma membrane mono-carboxylate transporters (MCTs) that enable lactate export from the cell and allow the cell to function without becoming acidotic [ 4 ]. Additional cancer cell metabolic adaptations include altered metabolism and uptake of certain amino acids [ 5 ]. From these observations, targeting the upregulated glucose uptake and glycolysis in cancer cells is thought of as adding a measure of selectivity to cancer therapy, while leaving the normal cells largely unaffected [ 6 ].…”

The Juggernaut of Adaptive Metabolism in Cancers: Implications and Therapeutic Targets

“…Targeting one or more of these entities by cutting off the glucose-molecule-derived energy and precursor molecule supply should then suppress the cancer cell proliferation, induce cell death, and thus inhibit tumor growth. However, in such a scenario, interestingly, the neoplastic cellular machinery instinctively switches to alternate metabolic pathways (such as glutamine metabolism) to derive cellular energy and maintain the supply of precursors for macromolecular biosynthesis [ 7 , 8 , 9 ] ( Figure 1 ). More recently, in the neoplastic tissues, other dimensions of the rewired metabolism, such as (1) adaptive changes in amino acid (glutamine), protein, lipid, and nucleotide metabolism; (2) altered propionate metabolism; and (3) isoforms of metabolic-pathway-related enzymes that support tumorigenesis, cancer progression and aggressiveness, and drug resistance, have garnered attention [ 7 , 9 , 10 ].…”

“…Dysregulated glutamine metabolism, as a hallmark of several cancers, was the focus of the review by Halama A and Suhre K [ 9 ]. It is evident that cancer cells derive their energy and maintain their supply of macromolecules for growth, survival, and proliferation by metabolizing glutamine when glucose is restricted in the cancer environment [ 9 ]. Hence, targeting and inhibiting glutamine metabolism could play key roles in limiting the growth of a malignant tumor [ 9 ].…”

“…It is evident that cancer cells derive their energy and maintain their supply of macromolecules for growth, survival, and proliferation by metabolizing glutamine when glucose is restricted in the cancer environment [ 9 ]. Hence, targeting and inhibiting glutamine metabolism could play key roles in limiting the growth of a malignant tumor [ 9 ]. However, the inhibition of glutamine metabolism in cancers leads to the utilization of alternate metabolic pathways for survival and growth [ 9 ].…”

“…Hence, targeting and inhibiting glutamine metabolism could play key roles in limiting the growth of a malignant tumor [ 9 ]. However, the inhibition of glutamine metabolism in cancers leads to the utilization of alternate metabolic pathways for survival and growth [ 9 ]. The authors provided an in-depth review of the role of dysregulated glutamine metabolism in several different cancers, different anti-neoplastic therapeutic targets in glutamine metabolism, alternative metabolic pathways activated upon the inhibition of glutamine metabolism, and the efficacy of combinatory/dual-pathway-targeting therapeutic interventions to improve the efficacy of anti-cancer treatments [ 9 ].…”