IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46572-6.html
   My bibliography  Save this article

Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability

Author

Listed:
  • Minhui Ye

    (Wuhan University
    Wuhan University)

  • Yingzhe Fang

    (Wuhan University
    Wuhan University)

  • Lu Chen

    (Wuhan University)

  • Zemin Song

    (Wuhan University)

  • Qing Bao

    (Wuhan University)

  • Fei Wang

    (ShanghaiTech University)

  • Hao Huang

    (Wuhan University)

  • Jin Xu

    (Wuhan University)

  • Ziwen Wang

    (Sun Yat-sen University Cancer Center)

  • Ruijing Xiao

    (Wuhan University)

  • Meng Han

    (Tsinghua University Technology Center for Protein Research)

  • Song Gao

    (Sun Yat-sen University Cancer Center)

  • Hudan Liu

    (Wuhan University)

  • Baishan Jiang

    (Wuhan University)

  • Guoliang Qing

    (Wuhan University
    Wuhan University
    Wuhan University)

Abstract

Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free deoxy-ribonucleoside triphosphates (dNTPs). How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins coordinate nucleotide synthesis and ROS generation to drive the development of numerous cancers. We herein perform a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven dependency. Mechanistically, MYC orchestrates the balance of two metabolic pathways that act in parallel, the NADPH oxidase 4 (NOX4)-ROS pathway and the Polo like kinase 1 (PLK1)-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as a potent, on-target degrader that depletes NUDT1 in vivo. Administration of LC-1-40 elicits excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.

Suggested Citation

  • Minhui Ye & Yingzhe Fang & Lu Chen & Zemin Song & Qing Bao & Fei Wang & Hao Huang & Jin Xu & Ziwen Wang & Ruijing Xiao & Meng Han & Song Gao & Hudan Liu & Baishan Jiang & Guoliang Qing, 2024. "Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46572-6
    DOI: 10.1038/s41467-024-46572-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46572-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-46572-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Helge Gad & Tobias Koolmeister & Ann-Sofie Jemth & Saeed Eshtad & Sylvain A. Jacques & Cecilia E. Ström & Linda M. Svensson & Niklas Schultz & Thomas Lundbäck & Berglind Osk Einarsdottir & Aljona Sale, 2014. "MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool," Nature, Nature, vol. 508(7495), pages 215-221, April.
    2. Liyuan Wang & Chan Chen & Zemin Song & Honghong Wang & Minghui Ye & Donghai Wang & Wenqian Kang & Hudan Liu & Guoliang Qing, 2022. "EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yangyang Ding & Xiang Gui & Xiang Chu & Yueyue Sun & Sixuan Zhang & Huan Tong & Wen Ju & Yue Li & Zengtian Sun & Mengdi Xu & Zhenyu Li & Robert K. Andrews & Elizabeth E. Gardiner & Lingyu Zeng & Kaili, 2023. "MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Yejinpeng Wang & Lingao Ju & Gang Wang & Kaiyu Qian & Wan Jin & Mingxing Li & Jingtian Yu & Yiliang Shi & Yongzhi Wang & Yi Zhang & Yu Xiao & Xinghuan Wang, 2023. "DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46572-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.