The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma

PLoS One. 2021 Nov 3;16(11):e0259241. doi: 10.1371/journal.pone.0259241. eCollection 2021.

Abstract

Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / administration & dosage*
  • Anilides / pharmacology
  • Animals
  • Benzeneacetamides / administration & dosage*
  • Benzeneacetamides / pharmacology
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Synergism
  • Everolimus / administration & dosage*
  • Everolimus / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glucose / metabolism
  • Glutaminase / antagonists & inhibitors
  • Glutamine / metabolism
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / metabolism
  • Mice
  • Pyridines / administration & dosage*
  • Pyridines / pharmacology
  • Signal Transduction / drug effects
  • Thiadiazoles / administration & dosage*
  • Thiadiazoles / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Anilides
  • Benzeneacetamides
  • CB-839
  • Pyridines
  • Thiadiazoles
  • Glutamine
  • cabozantinib
  • Everolimus
  • GLS protein, human
  • Glutaminase
  • Glucose

Grant support

This study was funded by Calithera Biosciences, Inc. in the form of salaries for all of the authors. The specific roles of the authors are articulated in the author contributions section. The founder had a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript.