Targeting glutamine metabolism slows soft tissue sarcoma growth

Nat Commun. 2020 Jan 24;11(1):498. doi: 10.1038/s41467-020-14374-1.


Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. However, glutamine dependence can be highly variable between in vitro and in vivo settings, based on surrounding microenvironments and complex adaptive responses to glutamine deprivation. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. Therefore, it is critical to identify alternate therapies to improve patient outcomes. Using autochthonous STS murine models and unbiased metabolomics, we demonstrate that glutamine metabolism supports sarcomagenesis. STS subtypes expressing elevated glutaminase (GLS) levels are highly sensitive to glutamine starvation. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, successfully inhibits undifferentiated pleomorphic sarcoma (UPS) tumour growth. We reveal glutamine metabolism as critical for sarcomagenesis, with CB-839 exhibiting potent therapeutic potential.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allografts / drug effects
  • Allografts / metabolism
  • Animals
  • Benzeneacetamides / pharmacology
  • Benzeneacetamides / therapeutic use
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Glutaminase / antagonists & inhibitors
  • Glutaminase / genetics
  • Glutaminase / metabolism
  • Glutamine / metabolism*
  • Mice
  • Nucleosides / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sarcoma / diagnostic imaging
  • Sarcoma / drug therapy
  • Sarcoma / metabolism*
  • Sarcoma / pathology*
  • Thiadiazoles / pharmacology
  • Thiadiazoles / therapeutic use
  • Tomography, X-Ray Computed


  • Benzeneacetamides
  • CB-839
  • Enzyme Inhibitors
  • Nucleosides
  • RNA, Messenger
  • Thiadiazoles
  • Glutamine
  • Glutaminase