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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
Stockholm University, Faculty of Science, Department of Analytical Chemistry.
Stockholm University, Faculty of Science, Department of Analytical Chemistry.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2014 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, no 7495, 215-221 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 508, no 7495, 215-221 p.
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:su:diva-102367DOI: 10.1038/nature13181ISI: 000333979900038OAI: oai:DiVA.org:su-102367DiVA: diva2:709927
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Totalt 57 författare.

Available from: 2014-04-02 Created: 2014-04-03 Last updated: 2017-12-05Bibliographically approved

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Saleh, AljonaGranelli, IngridGustafsson, RobertStenmark, PålHäggblad, MariaMartens, UlfLundgren, Bo
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Department of Analytical ChemistryDepartment of Biochemistry and BiophysicsDepartment of Genetics, Microbiology and ToxicologyScience for Life Laboratory (SciLifeLab)
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