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

Glutamine antagonists DON and JHU-083 suppress tumor growth in adrenocortical carcinoma, with DON linked to selective blockade of glutamine-fueled de novo nucleotide biosynthesis.

• Why it matters: ACC metabolism is poorly understood, and identifying glutamine-linked vulnerabilities could enable targeted therapies beyond current options.
• What they did: The work integrated transcriptional profiling across human and mouse ACC, targeted tissue metabolomics in a mouse ACC model, and untargeted serum metabolomics from a large patient cohort, then tested DON and JHU-083 and probed mechanism.
• The result: DON primarily inhibited glutamine-fueled de novo nucleotide biosynthesis, induced DNA damage, and showed potent synergism with DNA damage response pathway inhibition, supporting glutamine metabolism as a therapeutic dependency in ACC.

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