Glutamine antagonism suppresses tumor growth in adrenocortical carcinoma through inhibition of de novo nucleotide biosynthesis
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Dysregulation of cellular metabolism is a hallmark of cancer, which remains poorly understood in adrenocortical carcinoma (ACC). Here, we dissected ACC metabolism by integrating transcriptional profiling from human and mouse ACC, targeted tissue metabolomics from a mouse ACC model, and untargeted serum metabolomics from a large patient cohort, providing cross-species validation of metabolic rewiring in ACC. This study revealed global metabolic dysregulation, involving glutamine-dependent pathways such as non-essential amino-acid and hexosamine biosynthesis, nucleotide metabolism, and glutathione biosynthesis, suggesting glutamine catabolism is a critical metabolic vulnerability in ACC. Treatment with glutamine antagonists 6-Diazo-5-Oxo-L-Norleucine (DON) and JHU-083 elicited robust anti-tumor responses. Mechanistic studies revealed DON’s anti-tumor effect was primarily driven by selective inhibition of glutamine-fueled de novo nucleotide biosynthesis. Additionally, DON led to DNA damage, which yielded potent synergism with inhibition of the DNA damage response pathway. Collectively, this work highlights glutamine metabolism as a central metabolic dependency and therapeutic target in ACC.
Highlights
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Mouse and human ACC share conserved transcriptional–metabolic programs, revealing Gln metabolism as a central, targetable vulnerability.
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Targeted tissue metabolomic analysis in a mouse model of ACC validates dysregulation in Gln-dependent metabolic pathways.
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Targeting of Gln metabolism with JHU-083 (6-diazo-5-oxo-L-norleucine (DON) pro-drug) achieves marked inhibition of tumor growth in vivo .
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High expression of Gln-metabolizing genes mediating de novo nucleotide biosynthesis is associated with poor prognosis in ACC.
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DON drives nucleotide depletion and DNA damage, leading to potent synergy with inhibition of the DNA damage response.
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Untargeted serum metabolomic analysis in a large cohort of patients with adrenal tumors demonstrates dysregulation of Gln and nucleotide metabolism in ACC.
