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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.

Journal article
Authors 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
Thomas Helleday
Published in Nature
Volume 508
Issue 7495
Pages 215-21
ISSN 1476-4687
Publication year 2014
Published at Institute of Clinical Sciences, Department of Surgery
Pages 215-21
Language en
Links dx.doi.org/10.1038/nature13181
Subject categories Cancer and Oncology

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.

Page Manager: Webmaster|Last update: 9/11/2012
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