MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

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 Saleh, Camilla Göktürk, Pawel Baranczewski, Richard Svensson, Ronnie P.-A. Berntsson, Robert Gustafsson, Kia Strömberg, Kumar Sanjiv, Marie-Caroline Jacques-Cordonnier, Matthieu Desroses, Anna-Lena Gustavsson, Roger Olofsson, Fredrik Johansson, Evert J. Homan, Olga Loseva, Lars Bräutigam, Lars Johansson, Andreas Höglund, Anna Hagenkort, Therese Pham, Mikael Altun, Fabienne Z. Gaugaz, Svante Vikingsson, Bastiaan Evers, Martin Henriksson, Karl S. A. Vallin, Olov A. Wallner, Lars G. J. Hammarström, Elisee Wiita, Ingrid Almlöf, Christina Kalderén, Hanna Axelsson, Tatjana Djureinovic, Jordi Carreras Puigvert, Maria Häggblad, Fredrik Jeppsson, Ulf Martens, Cecilia Lundin, Bo Lundgren, Ingrid Granelli, Annika Jenmalm Jensen, Per Artursson, Jonas A. Nilsson, Pål Stenmark, Martin Scobie, Ulrika Warpman Berglund and Thomas Helleday ()
Additional contact information
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
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
Richard Svensson: Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, 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
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
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
Svante Vikingsson: Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
Bastiaan Evers: Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, Sweden
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
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
Tatjana Djureinovic: Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden
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
Per Artursson: Chemical Biology Consortium Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Stockholm, 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

Nature, 2014, vol. 508, issue 7495, 215-221

Abstract: 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.

Date: 2014
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/nature13181 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:508:y:2014:i:7495:d:10.1038_nature13181

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature13181

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().