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

doi:10.1038/nature13181

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

University of Iceland

University of Iceland

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	215-221
Number of pages	7
Journal	Nature
Volume	508
Issue number	7495
DOIs	https://doi.org/10.1038/nature13181
Publication status	Published - 10 Apr 2014

Bibliographical note

Funding Information: Acknowledgements We thank scientists at BESSY, ESRF, Max-Lab and the Swiss Light Source for structural biology data collection support, PSF for protein purification, GE Healthcare for instrument access, HTSRC (Rockefeller University) for iTC200 calorimeter access, S. Nordstrand for animal support, and L. Ny, U. Stierner and J. Mattsson for discussions. The Helleday Laboratory is primarily funded by the Torsten and Ragnar Söderberg Foundation (T.H.). This project is primarily supported by The Knut and Alice Wallenberg Foundation. Further support was received from the Swedish Research Council (T.H., A.J.J., P.A., P.S., J.A.N.), the European Research Council (T.H.), Swedish Cancer Society (T.H., J.A.N.), the Swedish Children’s Cancer Foundation (T.H.), AFA insurance (T.H.), the Swedish Pain Relief Foundation (T.H.), The Cancer Society in Stockholm (T.H.), the Wenner-Gren Foundations (P.S.), the Swedish Foundation for Strategic Research (P.S.), the Dutch Cancer Society (B.E.), EMBO LTF (R.B.), Region Västra Götaland (J.A.N.), BioCARE (J.A.N.), the Swiss National Science Foundation (F.Z.G.) and the Nicholson Exchange Program (T.L.). Chemical Biology Consortium Sweden (CBCS) is primarily funded by the Swedish Research Council. CBCS acknowledge Swedish Orphan Biovitrum for their donation of a small-molecule infrastructure including a compound collection. Publisher Copyright: © 2014 Macmillan Publishers Limited. All rights reserved.

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Gad, H., Koolmeister, T., Jemth, A. S., Eshtad, S., Jacques, S. A., Ström, C. E., Svensson, L. M., Schultz, N., Lundbäck, T., Einarsdottir, B. O., Saleh, A., Göktürk, C., Baranczewski, P., Svensson, R., Berntsson, R. P. A., Gustafsson, R., Strömberg, K., Sanjiv, K., Jacques-Cordonnier, M. C., ... Granelli, I. (2014). MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature, 508(7495), 215-221. https://doi.org/10.1038/nature13181

@article{84626f76996b4fbeb0f1e823e2603aae,

title = "MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool",

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.",

author = "Helge Gad and Tobias Koolmeister and Jemth, \{Ann Sofie\} and Saeed Eshtad and Jacques, \{Sylvain A.\} and Str{\"o}m, \{Cecilia E.\} and Svensson, \{Linda M.\} and Niklas Schultz and Thomas Lundb{\"a}ck and Einarsdottir, \{Berglind Osk\} and Aljona Saleh and Camilla G{\"o}kt{\"u}rk and Pawel Baranczewski and Richard Svensson and Berntsson, \{Ronnie P.A.\} and Robert Gustafsson and Kia Str{\"o}mberg and Kumar Sanjiv and Jacques-Cordonnier, \{Marie Caroline\} and Matthieu Desroses and Gustavsson, \{Anna Lena\} and Roger Olofsson and Fredrik Johansson and Homan, \{Evert J.\} and Olga Loseva and Lars Br{\"a}utigam and Lars Johansson and Andreas H{\"o}glund and Anna Hagenkort and Therese Pham and Mikael Altun and Gaugaz, \{Fabienne Z.\} and Svante Vikingsson and Bastiaan Evers and Martin Henriksson and Vallin, \{Karl S.A.\} and Wallner, \{Olov A.\} and Hammarstr{\"o}m, \{Lars G.J.\} and Elisee Wiita and Ingrid Alml{\"o}f and Christina Kalder{\'e}n and Hanna Axelsson and Tatjana Djureinovic and Puigvert, \{Jordi Carreras\} and Maria H{\"a}ggblad and Fredrik Jeppsson and Ulf Martens and Cecilia Lundin and Bo Lundgren and Ingrid Granelli",

note = "Funding Information: Acknowledgements We thank scientists at BESSY, ESRF, Max-Lab and the Swiss Light Source for structural biology data collection support, PSF for protein purification, GE Healthcare for instrument access, HTSRC (Rockefeller University) for iTC200 calorimeter access, S. Nordstrand for animal support, and L. Ny, U. Stierner and J. Mattsson for discussions. The Helleday Laboratory is primarily funded by the Torsten and Ragnar S{\"o}derberg Foundation (T.H.). This project is primarily supported by The Knut and Alice Wallenberg Foundation. Further support was received from the Swedish Research Council (T.H., A.J.J., P.A., P.S., J.A.N.), the European Research Council (T.H.), Swedish Cancer Society (T.H., J.A.N.), the Swedish Children{\textquoteright}s Cancer Foundation (T.H.), AFA insurance (T.H.), the Swedish Pain Relief Foundation (T.H.), The Cancer Society in Stockholm (T.H.), the Wenner-Gren Foundations (P.S.), the Swedish Foundation for Strategic Research (P.S.), the Dutch Cancer Society (B.E.), EMBO LTF (R.B.), Region V{\"a}stra G{\"o}taland (J.A.N.), BioCARE (J.A.N.), the Swiss National Science Foundation (F.Z.G.) and the Nicholson Exchange Program (T.L.). Chemical Biology Consortium Sweden (CBCS) is primarily funded by the Swedish Research Council. CBCS acknowledge Swedish Orphan Biovitrum for their donation of a small-molecule infrastructure including a compound collection. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",

year = "2014",

month = apr,

day = "10",

doi = "10.1038/nature13181",

language = "English",

volume = "508",

pages = "215--221",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7495",

}

Gad, H, Koolmeister, T, Jemth, AS, Eshtad, S, Jacques, SA, Ström, CE, Svensson, LM, Schultz, N, Lundbäck, T, Einarsdottir, BO, Saleh, A, Göktürk, C, Baranczewski, P, Svensson, R, Berntsson, RPA, Gustafsson, R, Strömberg, K, Sanjiv, K, Jacques-Cordonnier, MC, Desroses, M, Gustavsson, AL, Olofsson, R, Johansson, F, Homan, EJ, Loseva, O, Bräutigam, L, Johansson, L, Höglund, A, Hagenkort, A, Pham, T, Altun, M, Gaugaz, FZ, Vikingsson, S, Evers, B, Henriksson, M, Vallin, KSA, Wallner, OA, Hammarström, LGJ, Wiita, E, Almlöf, I, Kalderén, C, Axelsson, H, Djureinovic, T, Puigvert, JC, Häggblad, M, Jeppsson, F, Martens, U, Lundin, C, Lundgren, B & Granelli, I 2014, 'MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool', Nature, vol. 508, no. 7495, pp. 215-221. https://doi.org/10.1038/nature13181

TY - JOUR

T1 - MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

AU - Gad, Helge

AU - Koolmeister, Tobias

AU - Jemth, Ann Sofie

AU - Eshtad, Saeed

AU - Jacques, Sylvain A.

AU - Ström, Cecilia E.

AU - Svensson, Linda M.

AU - Schultz, Niklas

AU - Lundbäck, Thomas

AU - Einarsdottir, Berglind Osk

AU - Saleh, Aljona

AU - Göktürk, Camilla

AU - Baranczewski, Pawel

AU - Svensson, Richard

AU - Berntsson, Ronnie P.A.

AU - Gustafsson, Robert

AU - Strömberg, Kia

AU - Sanjiv, Kumar

AU - Jacques-Cordonnier, Marie Caroline

AU - Desroses, Matthieu

AU - Gustavsson, Anna Lena

AU - Olofsson, Roger

AU - Johansson, Fredrik

AU - Homan, Evert J.

AU - Loseva, Olga

AU - Bräutigam, Lars

AU - Johansson, Lars

AU - Höglund, Andreas

AU - Hagenkort, Anna

AU - Pham, Therese

AU - Altun, Mikael

AU - Gaugaz, Fabienne Z.

AU - Vikingsson, Svante

AU - Evers, Bastiaan

AU - Henriksson, Martin

AU - Vallin, Karl S.A.

AU - Wallner, Olov A.

AU - Hammarström, Lars G.J.

AU - Wiita, Elisee

AU - Almlöf, Ingrid

AU - Kalderén, Christina

AU - Axelsson, Hanna

AU - Djureinovic, Tatjana

AU - Puigvert, Jordi Carreras

AU - Häggblad, Maria

AU - Jeppsson, Fredrik

AU - Martens, Ulf

AU - Lundin, Cecilia

AU - Lundgren, Bo

AU - Granelli, Ingrid

N1 - Funding Information: Acknowledgements We thank scientists at BESSY, ESRF, Max-Lab and the Swiss Light Source for structural biology data collection support, PSF for protein purification, GE Healthcare for instrument access, HTSRC (Rockefeller University) for iTC200 calorimeter access, S. Nordstrand for animal support, and L. Ny, U. Stierner and J. Mattsson for discussions. The Helleday Laboratory is primarily funded by the Torsten and Ragnar Söderberg Foundation (T.H.). This project is primarily supported by The Knut and Alice Wallenberg Foundation. Further support was received from the Swedish Research Council (T.H., A.J.J., P.A., P.S., J.A.N.), the European Research Council (T.H.), Swedish Cancer Society (T.H., J.A.N.), the Swedish Children’s Cancer Foundation (T.H.), AFA insurance (T.H.), the Swedish Pain Relief Foundation (T.H.), The Cancer Society in Stockholm (T.H.), the Wenner-Gren Foundations (P.S.), the Swedish Foundation for Strategic Research (P.S.), the Dutch Cancer Society (B.E.), EMBO LTF (R.B.), Region Västra Götaland (J.A.N.), BioCARE (J.A.N.), the Swiss National Science Foundation (F.Z.G.) and the Nicholson Exchange Program (T.L.). Chemical Biology Consortium Sweden (CBCS) is primarily funded by the Swedish Research Council. CBCS acknowledge Swedish Orphan Biovitrum for their donation of a small-molecule infrastructure including a compound collection. Publisher Copyright: © 2014 Macmillan Publishers Limited. All rights reserved.

PY - 2014/4/10

Y1 - 2014/4/10

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84899619506

U2 - 10.1038/nature13181

DO - 10.1038/nature13181

M3 - Article

C2 - 24695224

SN - 0028-0836

VL - 508

SP - 215

EP - 221

JO - Nature

JF - Nature

IS - 7495

ER -

MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Abstract

Bibliographical note

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