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Nucleotide metabolism: a pan-cancer metabolic dependency

Nature Reviews Cancer volume 23, pages 275–294 (2023)Cite this article

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Abstract

Metabolic alterations are a key hallmark of cancer cells, and the augmented synthesis and use of nucleotide triphosphates is a critical and universal metabolic dependency of cancer cells across different cancer types and genetic backgrounds. Many of the aggressive behaviours of cancer cells, including uncontrolled proliferation, chemotherapy resistance, immune evasion and metastasis, rely heavily on augmented nucleotide metabolism. Furthermore, most of the known oncogenic drivers upregulate nucleotide biosynthetic capacity, suggesting that this phenotype is a prerequisite for cancer initiation and progression. Despite the wealth of data demonstrating the efficacy of nucleotide synthesis inhibitors in preclinical cancer models and the well-established clinical use of these drugs in certain cancer settings, the full potential of these agents remains unrealized. In this Review, we discuss recent studies that have generated mechanistic insights into the diverse biological roles of hyperactive cancer cell nucleotide metabolism. We explore opportunities for combination therapies that are highlighted by these recent advances and detail key questions that remain to be answered, with the goal of informing urgently warranted future studies.

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Fig. 1: Biosynthetic pathways for pyrimidine and purine nucleotides, relevant inhibitors and oncogenic regulators.
Fig. 2: Nucleotides fuel cancer cell growth and proliferation.
Fig. 3: Altered nucleoside handling facilitates cancer cell immune evasion.
Fig. 4: Supraphysiological GTP abundance promotes metastasis through the activation of RHO-family GTPases.
Fig. 5: Hyperactive nucleotide synthesis confers resistance to a range of therapeutic interventions.

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Acknowledgements

These studies are supported by F30CA265277 to N.J.M. and R01CA163649, R01CA270234, R01CA210439, R01CA216853, R01CA256911 and U54CA274329 to P.K.S. from the National Cancer Institute of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA

    Nicholas J. Mullen

  2. Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Pankaj K. Singh

  3. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Pankaj K. Singh

  4. OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Pankaj K. Singh

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  1. Nicholas J. Mullen
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N.J.M. and P.K.S. performed the literature search and developed the outline. N.J.M. developed the initial draft. P.K.S. edited the manuscript, added further content and provided mentoring and supervision.

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Correspondence to Pankaj K. Singh.

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Mullen, N.J., Singh, P.K. Nucleotide metabolism: a pan-cancer metabolic dependency. Nat Rev Cancer 23, 275–294 (2023). https://doi.org/10.1038/s41568-023-00557-7

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