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

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.

Decrease of Intracellular Glutamine by STF-62247 Results in the Accumulation of Lipid Droplets in von Hippel-Lindau Deficient Cells

“…The drop of glutamate and glutamine observed in VHL- ccRCC cells in response to STF-62247 was particularly interesting since these tumors rely on glutamine for growth and proliferation. In fact, glutaminase inhibitors showed anti-proliferative activity in vitro and in vivo in mice in a wide range of cancer models including RCC ( 33 , 58 , 59 ). However, clinical trials using GLS inhibitor Telaglenastat (CB-839) combined with the mTOR inhibitor everolimus showed a modest improvement of progression-free survival (PFS) from 1.9 months to 3.8 months while it fails to increase PFS in advanced ccRCC in combination with cabozantinib ( 33 ).…”

“…In fact, glutaminase inhibitors showed anti-proliferative activity in vitro and in vivo in mice in a wide range of cancer models including RCC ( 33 , 58 , 59 ). However, clinical trials using GLS inhibitor Telaglenastat (CB-839) combined with the mTOR inhibitor everolimus showed a modest improvement of progression-free survival (PFS) from 1.9 months to 3.8 months while it fails to increase PFS in advanced ccRCC in combination with cabozantinib ( 33 ). Our study demonstrated that STF-62247 significantly decreased intracellular levels of glutamine and glutamate without affecting GLS activity, ATP levels, mitochondrial oxygen consumption or mitochondrial membrane potential (data not shown) in VHL- cells.…”

“…Inside mitochondria, glutamine is converted into glutamate by the glutaminase (GLS1), which can then enter Krebs cycle. Inhibitors of GLS1 have been shown to repress cancer growth in tumors addicted to glutamine ( 24 , 25 , 32 , 33 ). Finally, glutamine goes through reductive carboxylation to form citrate and support fatty acid production, particularly in VHL-deficient RCC when HIF-2α is overexpressed ( 24 ).…”

Next Wave of Targets in the Treatment of Advanced Renal Cell Carcinoma

“…Cabozantinib inhibits the growth factor receptors VEGFR, MET and AXL and has downstream effects on the PI3K/AKT/mTOR pathway, leading to a decreased glucose utilization. In a preclinical model, the dual inhibition of glutamine and glucose metabolism showed enhanced anti-tumor activity [ 54 ].…”

Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma

“…This increase in glutamine metabolism fuels tumor cell proliferation and survival and is dependent on the catalytic activity of the enzyme glutaminase . Renal cell carcinoma cell lines have been shown to overexpress glutaminase …”