MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

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Gad, HelgeKarolinska Institutet,Karolinska Institute, Sweden (author)

MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Article/chapterEnglish2014

Publisher, publication year, extent ...

2014-04-02
Nature Publishing Group,2014
printrdacarrier

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LIBRIS-ID:oai:DiVA.org:liu-106278
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-106278URI
https://doi.org/10.1038/nature13181DOI
https://gup.ub.gu.se/publication/197278URI
http://kipublications.ki.se/Default.aspx?queryparsed=id:128621409URI
https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-102367URI
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-224325URI

Supplementary language notes

Language:English
Summary in:English

Part of subdatabase

SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

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 bindin 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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
NATURVETENSKAP Biologi hsv//swe
NATURAL SCIENCES Biological Sciences hsv//eng
MEDICINE
MEDICIN
Biochemistry

Added entries (persons, corporate bodies, meetings, titles ...)

Koolmeister, TobiasKarolinska Institutet,Karolinska Institute, Sweden (author)
Jemth, Ann-SofieKarolinska Institutet,Karolinska Institute, Sweden (author)
Eshtad, SaeedKarolinska Institutet,Karolinska Institute, Sweden (author)
Jacques, Sylvain A.Karolinska Institute, Sweden (author)
Ström, Cecilia E.Karolinska Institute, Sweden (author)
Svensson, Linda M.Stockholms universitet,Institutionen för biokemi och biofysik (author)
Schultz, NiklasKarolinska Institutet,Karolinska Institute, Sweden (author)
Lundbäck, ThomasKarolinska Institutet,Karolinska Institute, Sweden (author)
Einarsdottir, Berglind Osk,1979Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery,University of Gothenburg, Sweden; Sahlgrenska University Hospital, Sweden(Swepub:gu)xoskbe (author)
Saleh, AljonaStockholms universitet,Karolinska Institutet,Stockholm University, Sweden,Karolinska Institute, Sweden,Institutionen för analytisk kemi(Swepub:uu)aljsa108 (author)
Göktürk, CamillaKarolinska Institutet,Karolinska Institute, Sweden (author)
Baranczewski, PawelUppsala universitet,Karolinska Institutet,Karolinska Institute, Sweden Uppsala University, Sweden,Institutionen för farmaci(Swepub:uu)pawba132 (author)
Svensson, RichardUppsala universitet,Institutionen för farmaci(Swepub:uu)ricsv977 (author)
Berntsson, Ronnie P.-A.Uppsala universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Institutionen för farmaci(Swepub:uu)perartur (author)
Gustafsson, RobertStockholms universitet,Institutionen för biokemi och biofysik(Swepub:su)rogu0454 (author)
Strömberg, KiaKarolinska Institutet,Karolinska Institute, Sweden (author)
Sanjiv, KumarKarolinska Institute, Sweden (author)
Jacques-Cordonnier, Marie-CarolineKarolinska Institute, Sweden (author)
Desroses, MatthieuKarolinska Institutet,Karolinska Institute, Sweden (author)
Gustavsson, Anna-LenaKarolinska Institutet,Karolinska Institute, Sweden (author)
Olofsson, Roger,1978Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery,University of Gothenburg, Sweden; Sahlgrenska University Hospital, Sweden(Swepub:gu)xoloro (author)
Johansson, FredrikStockholms universitet,Institutionen för genetik, mikrobiologi och toxikologi(Swepub:su)fjoha (author)
Homan, Evert J.Karolinska Institutet,Karolinska Institute, Sweden (author)
Loseva, OlgaKarolinska Institutet,Karolinska Institute, Sweden (author)
Bräutigam, LarsKarolinska Institutet,Karolinska Institute, Sweden (author)
Johansson, LarsKarolinska Institutet,Karolinska Institute, Sweden(Swepub:gu)xjohay (author)
Höglund, AndreasKarolinska Institutet,Karolinska Institute, Sweden (author)
Hagenkort, AnnaKarolinska Institutet,Karolinska Institute, Sweden (author)
Pham, ThereseKarolinska Institutet,Karolinska Institute, Sweden (author)
Altun, MikaelKarolinska Institutet,Karolinska Institute, Sweden (author)
Gaugaz, Fabienne Z.Uppsala universitet,Karolinska Institutet,Karolinska Institute, Sweden; Uppsala University, Sweden,Institutionen för farmaci(Swepub:uu)fabga688 (author)
Vikingsson, SvanteLinköpings universitet,Avdelningen för läkemedelsforskning,Hälsouniversitetet(Swepub:liu)svavi08 (author)
Evers, BastiaanKarolinska Institute, Sweden (author)
Henriksson, MartinKarolinska Institutet,Karolinska Institute, Sweden (author)
Vallin, Karl S. A.Karolinska Institute, Sweden (author)
Wallner, Olov A.Karolinska Institutet,Karolinska Institute, Sweden (author)
Hammarström, Lars G. J.Karolinska Institute, Sweden (author)
Wiita, EliseeKarolinska Institutet,Karolinska Institute, Sweden (author)
Almlöf, IngridKarolinska Institutet,Karolinska Institute, Sweden (author)
Kalderén, ChristinaKarolinska Institutet,Karolinska Institute, Sweden (author)
Axelsson, HannaKarolinska Institutet,Karolinska Institute, Sweden (author)
Djureinovic, TatjanaStockholms universitet,Institutionen för genetik, mikrobiologi och toxikologi(Swepub:uu)tatdj291 (author)
Carreras Puigvert, JordiKarolinska Institutet,Karolinska Institute, Sweden (author)
Häggblad, MariaStockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)(Swepub:su)maha7002 (author)
Jeppsson, FredrikKarolinska Institute, Sweden (author)
Martens, UlfStockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)(Swepub:su)ulma3535 (author)
Lundin, CeciliaKarolinska Institute, Sweden (author)
Lundgren, BoStockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)(Swepub:su)bolu7255 (author)
Granelli, IngridStockholms universitet,Institutionen för analytisk kemi(Swepub:su)igran (author)
Jenmalm Jensen, AnnikaKarolinska Institutet,Karolinska Institute, Sweden (author)
Artursson, PerKarolinska Institute, Sweden; Uppsala University, Sweden (author)
Nilsson, Jonas A,1971Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery,University of Gothenburg, Sweden, Sahlgrens University Hospital, Sweden(Swepub:gu)xnijon (author)
Stenmark, PålStockholms universitet,Institutionen för biokemi och biofysik(Swepub:su)stenm (author)
Scobie, MartinKarolinska Institutet,Karolinska Institute, Sweden (author)
Warpman Berglund, UlrikaKarolinska Institutet,Karolinska Institute, Sweden (author)
Helleday, ThomasKarolinska Institutet,Karolinska Institute, Sweden (author)
Karolinska InstitutetKarolinska Institute, Sweden (creator_code:org_t)

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In:Nature: Nature Publishing Group508:7495, s. 215-2210028-08361476-4687

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By the author/editor: Gad, Helge; Koolmeister, Tob ...; Jemth, Ann-Sofie; Eshtad, Saeed; Jacques, Sylvain ...; Ström, Cecilia E ...; show more...; Svensson, Linda ...; Schultz, Niklas; Lundbäck, Thomas; Einarsdottir, Be ...; Saleh, Aljona; Göktürk, Camilla; Baranczewski, Pa ...; Svensson, Richar ...; Berntsson, Ronni ...; Gustafsson, Robe ...; Strömberg, Kia; Sanjiv, Kumar; Jacques-Cordonni ...; Desroses, Matthi ...; Gustavsson, Anna ...; Olofsson, Roger, ...; Johansson, Fredr ...; Homan, Evert J.; Loseva, Olga; Bräutigam, Lars; Johansson, Lars; Höglund, Andreas; Hagenkort, Anna; Pham, Therese; Altun, Mikael; Gaugaz, Fabienne ...; Vikingsson, Svan ...; Evers, Bastiaan; Henriksson, Mart ...; Vallin, Karl S. ...; Wallner, Olov A.; Hammarström, Lar ...; Wiita, Elisee; Almlöf, Ingrid; Kalderén, Christ ...; Axelsson, Hanna; Djureinovic, Tat ...; Carreras Puigver ...; Häggblad, Maria; Jeppsson, Fredri ...; Martens, Ulf; Lundin, Cecilia; Lundgren, Bo; Granelli, Ingrid; Jenmalm Jensen, ...; Artursson, Per; Nilsson, Jonas A ...; Stenmark, Pål; Scobie, Martin; Warpman Berglund ...; Helleday, Thomas; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...

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