Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy

Trends Cancer. 2021 Aug;7(8):790-804. doi: 10.1016/j.trecan.2021.04.003. Epub 2021 May 18.

Abstract

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.

Keywords: CB-839; JHU083; cancer metabolism; glutaminase; glutamine; immunometabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzeneacetamides / pharmacology
  • Benzeneacetamides / therapeutic use
  • Carcinogenesis / drug effects
  • Carcinogenesis / immunology
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Clinical Trials as Topic
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Glutaminase / antagonists & inhibitors
  • Glutaminase / metabolism
  • Glutamine / antagonists & inhibitors*
  • Glutamine / metabolism
  • Humans
  • NF-E2-Related Factor 2 / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oxidative Stress / drug effects
  • Thiadiazoles / pharmacology
  • Thiadiazoles / therapeutic use
  • Tumor Escape / drug effects
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • Antimetabolites, Antineoplastic
  • Benzeneacetamides
  • CB-839
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Thiadiazoles
  • Glutamine
  • GLS protein, human
  • GLS2 protein, human
  • Glutaminase