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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Author

Listed:
  • Helge Gad

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Tobias Koolmeister

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Ann-Sofie Jemth

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Saeed Eshtad

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Sylvain A. Jacques

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Cecilia E. Ström

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Linda M. Svensson

    (Stockholm University, S-106 91 Stockholm, Sweden)

  • Niklas Schultz

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Thomas Lundbäck

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Berglind Osk Einarsdottir

    (Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden)

  • Aljona Saleh

    (Stockholm University, S-106 91 Stockholm, Sweden)

  • Camilla Göktürk

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Pawel Baranczewski

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University, S-751 23 Uppsala, Sweden)

  • Richard Svensson

    (Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University, S-751 23 Uppsala, Sweden)

  • Ronnie P.-A. Berntsson

    (Stockholm University, S-106 91 Stockholm, Sweden)

  • Robert Gustafsson

    (Stockholm University, S-106 91 Stockholm, Sweden)

  • Kia Strömberg

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Kumar Sanjiv

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Marie-Caroline Jacques-Cordonnier

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Matthieu Desroses

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Anna-Lena Gustavsson

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Roger Olofsson

    (Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden)

  • Fredrik Johansson

    (Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden)

  • Evert J. Homan

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Olga Loseva

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Lars Bräutigam

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Lars Johansson

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Andreas Höglund

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Anna Hagenkort

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Therese Pham

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Mikael Altun

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Fabienne Z. Gaugaz

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University, S-751 23 Uppsala, Sweden)

  • Svante Vikingsson

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Clinical Pharmacology, Linköping University, S-58185 Linköping, Sweden)

  • Bastiaan Evers

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Present addresses: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.).)

  • Martin Henriksson

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Karl S. A. Vallin

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Olov A. Wallner

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Lars G. J. Hammarström

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Elisee Wiita

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Ingrid Almlöf

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Christina Kalderén

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Hanna Axelsson

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Tatjana Djureinovic

    (Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden
    Present addresses: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.).)

  • Jordi Carreras Puigvert

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Maria Häggblad

    (Science for Life Laboratory, RNAi Cell Screening Facility, Stockholm University, S-106 91 Stockholm, Sweden)

  • Fredrik Jeppsson

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Ulf Martens

    (Science for Life Laboratory, RNAi Cell Screening Facility, Stockholm University, S-106 91 Stockholm, Sweden)

  • Cecilia Lundin

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Bo Lundgren

    (Science for Life Laboratory, RNAi Cell Screening Facility, Stockholm University, S-106 91 Stockholm, Sweden)

  • Ingrid Granelli

    (Stockholm University, S-106 91 Stockholm, Sweden)

  • Annika Jenmalm Jensen

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Per Artursson

    (Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
    Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Uppsala University, S-751 23 Uppsala, Sweden)

  • Jonas A. Nilsson

    (Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden)

  • Pål Stenmark

    (Stockholm University, S-106 91 Stockholm, Sweden)

  • Martin Scobie

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Ulrika Warpman Berglund

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

  • Thomas Helleday

    (Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden)

Abstract

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:508:y:2014:i:7495:d:10.1038_nature13181
    DOI: 10.1038/nature13181
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    Cited by:

    1. 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.
    2. 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.

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