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Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy

Author

Listed:
  • Mylène Tajan

    (The Francis Crick Institute)

  • Marc Hennequart

    (The Francis Crick Institute)

  • Eric C. Cheung

    (The Francis Crick Institute)

  • Fabio Zani

    (The Francis Crick Institute)

  • Andreas K. Hock

    (Cancer Research UK Beatson Institute
    R&D, AstraZeneca)

  • Nathalie Legrave

    (The Francis Crick Institute)

  • Oliver D. K. Maddocks

    (Institute of Cancer Sciences, University of Glasgow)

  • Rachel A. Ridgway

    (Cancer Research UK Beatson Institute)

  • Dimitris Athineos

    (Cancer Research UK Beatson Institute)

  • Alejandro Suárez-Bonnet

    (The Royal Veterinary College)

  • Robert L. Ludwig

    (The Francis Crick Institute)

  • Laura Novellasdemunt

    (The Francis Crick Institute)

  • Nikolaos Angelis

    (The Francis Crick Institute)

  • Vivian S. W. Li

    (The Francis Crick Institute)

  • Georgios Vlachogiannis

    (The Institute of Cancer Research
    Imperial College London)

  • Nicola Valeri

    (The Institute of Cancer Research
    Imperial College London
    The Royal Marsden NHS Foundation Trust)

  • Nello Mainolfi

    (Raze Therapeutics, Inc.)

  • Vipin Suri

    (Raze Therapeutics, Inc.)

  • Adam Friedman

    (Raze Therapeutics, Inc.)

  • Mark Manfredi

    (Raze Therapeutics, Inc.)

  • Karen Blyth

    (Cancer Research UK Beatson Institute
    Institute of Cancer Sciences, University of Glasgow)

  • Owen J. Sansom

    (Cancer Research UK Beatson Institute
    Institute of Cancer Sciences, University of Glasgow)

  • Karen H. Vousden

    (The Francis Crick Institute)

Abstract

Many tumour cells show dependence on exogenous serine and dietary serine and glycine starvation can inhibit the growth of these cancers and extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression of the de novo serine synthesis pathway (SSP) enzymes or activation of oncogenes that drive enhanced serine synthesis. Here we show that inhibition of PHGDH, the first step in the SSP, cooperates with serine and glycine depletion to inhibit one-carbon metabolism and cancer growth. In vitro, inhibition of PHGDH combined with serine starvation leads to a defect in global protein synthesis, which blocks the activation of an ATF-4 response and more broadly impacts the protective stress response to amino acid depletion. In vivo, the combination of diet and inhibitor shows therapeutic efficacy against tumours that are resistant to diet or drug alone, with evidence of reduced one-carbon availability. However, the defect in ATF4-response seen in vitro following complete depletion of available serine is not seen in mice, where dietary serine and glycine depletion and treatment with the PHGDH inhibitor lower but do not eliminate serine. Our results indicate that inhibition of PHGDH will augment the therapeutic efficacy of a serine depleted diet.

Suggested Citation

  • Mylène Tajan & Marc Hennequart & Eric C. Cheung & Fabio Zani & Andreas K. Hock & Nathalie Legrave & Oliver D. K. Maddocks & Rachel A. Ridgway & Dimitris Athineos & Alejandro Suárez-Bonnet & Robert L. , 2021. "Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20223-y
    DOI: 10.1038/s41467-020-20223-y
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    Cited by:

    1. Ziwei Dai & Weiyan Zheng & Jason W. Locasale, 2022. "Amino acid variability, tradeoffs and optimality in human diet," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Gabrielle Manteaux & Alix Amsel & Blanche Riquier-Morcant & Jaime Prieto Romero & Laurie Gayte & Benjamin Fourneaux & Marion Larroque & Nadège Gruel & Chloé Quignot & Gaelle Perot & Solenn Jacq & Madi, 2024. "A metabolic crosstalk between liposarcoma and muscle sustains tumor growth," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Nicole Kiweler & Catherine Delbrouck & Vitaly I. Pozdeev & Laura Neises & Leticia Soriano-Baguet & Kim Eiden & Feng Xian & Mohaned Benzarti & Lara Haase & Eric Koncina & Maryse Schmoetten & Christian , 2022. "Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Li Luo & Xingyun Wu & Jiawu Fan & Lixia Dong & Mao Wang & Yan Zeng & Sijia Li & Wenyong Yang & Jingwen Jiang & Kui Wang, 2024. "FBXO7 ubiquitinates PRMT1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Kui Wang & Li Luo & Shuyue Fu & Mao Wang & Zihao Wang & Lixia Dong & Xingyun Wu & Lunzhi Dai & Yong Peng & Guobo Shen & Hai-Ning Chen & Edouard Collins Nice & Xiawei Wei & Canhua Huang, 2023. "PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Camilla Tombari & Alessandro Zannini & Rebecca Bertolio & Silvia Pedretti & Matteo Audano & Luca Triboli & Valeria Cancila & Davide Vacca & Manuel Caputo & Sara Donzelli & Ilenia Segatto & Simone Vodr, 2023. "Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    7. Marc Hennequart & Christiaan F. Labuschagne & Mylène Tajan & Steven E. Pilley & Eric C. Cheung & Nathalie M. Legrave & Paul C. Driscoll & Karen H. Vousden, 2021. "The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-10, December.

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