Glutaminolysis as a target for cancer therapy

Abstract

Cancer cells display an altered metabolic circuitry that is directly regulated by oncogenic mutations and loss of tumor suppressors. Mounting evidence indicates that altered glutamine metabolism in cancer cells has critical roles in supporting macromolecule biosynthesis, regulating signaling pathways, and maintaining redox homeostasis, all of which contribute to cancer cell proliferation and survival. Thus, intervention in these metabolic processes could provide novel approaches to improve cancer treatment. This review summarizes current findings on the role of glutaminolytic enzymes in human cancers and provides an update on the development of small molecule inhibitors to target glutaminolysis for cancer therapy.

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

“…Analysis of steady state metabolite levels using pathway enrichment revealed a diverse set of metabolic pathways altered in a MYC-dependent fashion in resistant cells relative to parental cells, as evidenced by the fact that reciprocal changes between the resistant and shMYC cells were observed (Figure 7A). Of note were alterations in glycolysis, serine, and glutamine metabolism, each of which has been implicated in MYC-driven oncogenesis (Jin et al, 2015; Pavlova and Thompson, 2016; Stine et al, 2015). Glycolysis-related gene sets were enriched in BRAFi/MEKi-resistant cell lines and human patient tumors (Figure 7B), and we observed modest MYC-dependent (as well as MYC-independent) changes in the expression of key early glycolytic enzymes (e.g., hexokinase 2 (HK2)) and in the steady-state levels of glycolytic intermediates, in particular, lactate (Figures 7B and S7B–D).…”

Metabolic Instruction of Immunity

“…Glutaminolysis in tumor cells is critical to replenish metabolites through anaplerotic reactions, which could result in competition for glutamine between tumor cells and TILs (Jin et al, 2015; Pérez-Escuredo et al, 2015). Glutamine controls mTOR activation in T cells and macrophages and is also a key substrate for protein O-GlcNAcylation and synthesis of S-2HG that regulate effector T cell function and differentiation (Sinclair et al, 2013; Swamy et al, 2016; Tyrakis et al, 2016).…”

Pheochromocytoma: The First Metabolic Endocrine Cancer

“…hexokinase 2, LDH, or PDK inhibitors) (85, 86). Another option is inhibitors of glutaminolysis or SLC1A5 glutamine transporter (87). Glucose and glutamine utilization is finely balanced and both nutrients function interdependently of tumor metabolism.…”