Glutamine antagonism suppresses tumor growth in adrenocortical carcinoma through inhibition of de novo nucleotide biosynthesis PMID: 41256360

ADC Targets in Oncology

2026-04-10

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

bioRxiv. 2025 Sep 29:2025.09.28.674326. doi: 10.1101/2025.09.28.674326.

Vasileios Chortis ¹ ² ³ ⁴ , Kleiton Silva Borges ¹ ² , Cong-Hui Yao ⁵ , Claudio Ribeiro ¹ ² , Luis Fernando Nagano ⁶ , Mesut Berber ¹ ² , Alessandro Prete ³ ⁴ ⁷ , Lukáš Najdekr ⁸ , Michail E Klontzas ⁹ , Andris Jankevics ⁸ , Pedro Vendramini ¹ ² , Jean Lucas Kremer ¹ ² , Liam Kelley ⁵ , Sathuwarman Raveenthiraraj ¹⁰ , Stylianos Tsagarakis ¹¹ , Magdalena Macech ¹² , Ivana D Pupovac ¹³ , Thomas G Papathomas ³ ¹⁴ , Betul Haykir ¹ ² , Catherine Winder ⁸ , Marcus Quinkler ¹⁵ , M Conall Dennedy ¹⁶ , Grethe Å Ueland ¹⁷ , Felix Beuschlein ¹⁸ ¹⁹ ²⁰ , Antoine Tabarin ²¹ , Martin Fassnacht ²² , Angela E Taylor ³ ⁴ , Darko Kastelan ¹³ , Urszula Ambroziak ¹² , Dimitra A Vassiliadi ¹¹ , Katja Kiseljak-Vassiliades ²³ , Irina Bancos ²⁴ , Diana L Carlone ¹ ² ²⁵ , Warwick B Dunn ⁸ ²⁶ , Wiebke Arlt ²⁷ ²⁸ , Marcia C Haigis ⁵ , David T Breault ¹ ² ²⁵

Affiliations

1. Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.
2. Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
3. Department of Metabolism and Systems Science, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK.
4. Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
5. Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
6. Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
7. National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK.
8. Phenome Centre Birmingham, School of Biosciences, University of Birmingham, Birmingham, UK.
9. Artificial Intelligence and Translational Imaging (ATI) Lab, Department of Radiology, School of Medicine, University of Crete, Heraklion, Greece.
10. Division of Newborn Medicine, Boston Children's Hospital, Boston, MA.
11. Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece.
12. Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland.
13. Department of Endocrinology, University Hospital Centre Zagreb, Zagreb, Croatia.
14. Department of Clinical Pathology, Vestre Viken HF, Norway.
15. Endocrinology in Charlottenburg, Berlin, Germany.
16. Department of Medicine, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Republic of Ireland.
17. Department of Medicine, section of Endocrinology, Haukeland University Hospital, Bergen, Norway.
18. Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitäts-Spital Zürich (USZ) und Universität Zürich (UZH), Zurich, Switzerland.
19. The LOOP Zurich - Medical Research Center, Zurich, Switzerland.
20. Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
21. Service d'Endocrinologie, Centre Hospitalier Universitaire, Hopital du Haut Leveque, Pessac, France.
22. Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.
23. Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO 80045, USA.
24. Division of Endocrinology, Metabolism, Diabetes and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
25. Harvard Stem Cell Institute, Cambridge, MA, USA.
26. Centre for Metabolomics Research, Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK.
27. Medical Research Council Laboratory of Medical Sciences, London, UK.
28. Institute of Clinical Sciences, Imperial College London, London, UK.

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.