Targeted inhibition of glutamine metabolism enhances the antitumor effect of selumetinib in KRAS-mutant NSCLC

https://doi.org/10.1016/j.tranon.2020.100920Get rights and content
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Highlights

  • The glutamine utilization of KRAS-mutant NSCLC is higher than that of KRAS wild-type.

  • Targeted GLS1 and MEK inhibition enhance antitumor activity in vitro and in vivo.

  • The therapeutic response can be well identified by 18F-FDG PET imaging.

  • Dual inhibition of GLS1 and MEK induce redox and energetic stress.

  • Dual inhibition of GLS1 and MEK suppress the phosphorylation of AKT.

Abstract

Regulated by the tumor microenvironment, the metabolic network of the tumor is reprogrammed, driven by oncogenes and tumor suppressor genes. The metabolic phenotype of tumors of different driven-genes and different tissue types is extremely heterogeneous. KRAS-mutant non-small cell lung cancer (NSCLC) has glutamine dependence. In this study, we demonstrated that glutamine utilization of KRAS-mutant NSCLC was higher than that of KRAS wild-type. CB839, an efficient glutaminase inhibitor, synergized with the MEK inhibitor selumetinib to enhance antitumor activity in KRAS-mutant NSCLC cells and xenografts, and the therapeutic response could be well identified by 18F-FDG PET imaging. Combination therapy induced redox stress, manifesting as a decrease in mitochondrial membrane potential and an increase in ROS levels, and energetic stress manifesting as suppression of glycolysis and glutamine degradation. The phosphorylation of AKT was also suppressed. These effects combined to induce autophagy and thereby caused cancer cell death. Our results suggest that dual inhibition of the MEK-ERK pathway and glutamine metabolism activated by KRAS mutation may be an effective treatment strategy for KRAS-driven NSCLC.

Keywords

KRAS
Glutaminase
Microenvironment
Autophagy

Abbreviations

NSCLC
non-small cell lung cancer
18F-FDG
18F-fluoro-2deoxyglucose
PET
positron emission tomography
18F-Gln
18F- (2S,4R)4-fluoroglutamine
GLS
glutaminase
IC50
the half maximal inhibitory concentration
CI
combination index
%ID/g
units of percent injected dose per gram
SUVmax
maximum standardized uptake value
PMR
partial metabolic remission

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