Glutamine antagonism suppresses tumor growth in adrenocortical carcinoma through inhibition of de novo nucleotide biosynthesis

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Abstract 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 Mouse and human ACC share conserved transcriptional–metabolic programs, revealing Gln metabolism as a central, targetable vulnerability. Targeted tissue metabolomic analysis in a mouse model of ACC validates dysregulation in Gln-dependent metabolic pathways. Targeting of Gln metabolism with JHU-083 (6-diazo-5-oxo-L-norleucine (DON) pro-drug) achieves marked inhibition of tumor growth in vivo . High expression of Gln-metabolizing genes mediating de novo nucleotide biosynthesis is associated with poor prognosis in ACC. DON drives nucleotide depletion and DNA damage, leading to potent synergy with inhibition of the DNA damage response. Untargeted serum metabolomic analysis in a large cohort of patients with adrenal tumors demonstrates dysregulation of Gln and nucleotide metabolism in ACC.

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