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; Thomas Helleday

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 DesrosesAnna-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

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

432 Citations (Scopus)

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)	215-21
Number of pages	7
Journal	Nature
Volume	508
Issue number	7495
DOIs	https://doi.org/10.1038/nature13181
Publication status	Published - 10 Apr 2014
Externally published	Yes

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10.1038/nature13181

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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., ... Helleday, T. (2014). MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature, 508(7495), 215-21. https://doi.org/10.1038/nature13181

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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. ",

keywords = "Animals, Catalytic Domain, Cell Death/drug effects, Cell Survival/drug effects, Crystallization, DNA Damage, DNA Repair Enzymes/antagonists & inhibitors, Deoxyguanine Nucleotides/metabolism, Enzyme Inhibitors/chemistry, Female, Humans, Male, Mice, Models, Molecular, Molecular Conformation, Molecular Targeted Therapy, Neoplasms/drug therapy, Nucleotides/metabolism, Oxidation-Reduction/drug effects, Phosphoric Monoester Hydrolases/antagonists & inhibitors, Pyrimidines/chemistry, Pyrophosphatases/antagonists & inhibitors, Reproducibility of Results, Xenograft Model Antitumor Assays",

author = "Helge Gad and Tobias Koolmeister and Ann-Sofie Jemth 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 Marie-Caroline Jacques-Cordonnier and Matthieu Desroses and Anna-Lena Gustavsson 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 and Jensen, {Annika Jenmalm} and Per Artursson and Nilsson, {Jonas A} and P{\aa}l Stenmark and Martin Scobie and Berglund, {Ulrika Warpman} and Thomas Helleday",

year = "2014",

month = apr,

day = "10",

doi = "10.1038/nature13181",

language = "English",

volume = "508",

pages = "215--21",

journal = "Nature",

issn = "0028-0836",

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Gad, H, Koolmeister, T, Jemth, A-S, Eshtad, S, Jacques, SA, Ström, CE, Svensson, LM, Schultz, N, Lundbäck, T, Einarsdottir, BO, Saleh, A, Göktürk, C, Baranczewski, P, Svensson, R, Berntsson, RP-A, Gustafsson, R, Strömberg, K, Sanjiv, K, Jacques-Cordonnier, M-C, Desroses, M, Gustavsson, A-L, 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, Jensen, AJ, Artursson, P, Nilsson, JA, Stenmark, P, Scobie, M, Berglund, UW & Helleday, T 2014, 'MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool', Nature, vol. 508, no. 7495, pp. 215-21. 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

AU - Jensen, Annika Jenmalm

AU - Artursson, Per

AU - Nilsson, Jonas A

AU - Stenmark, Pål

AU - Scobie, Martin

AU - Berglund, Ulrika Warpman

AU - Helleday, Thomas

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.

KW - Animals

KW - Catalytic Domain

KW - Cell Death/drug effects

KW - Cell Survival/drug effects

KW - Crystallization

KW - DNA Damage

KW - DNA Repair Enzymes/antagonists & inhibitors

KW - Deoxyguanine Nucleotides/metabolism

KW - Enzyme Inhibitors/chemistry

KW - Female

KW - Humans

KW - Male

KW - Mice

KW - Models, Molecular

KW - Molecular Conformation

KW - Molecular Targeted Therapy

KW - Neoplasms/drug therapy

KW - Nucleotides/metabolism

KW - Oxidation-Reduction/drug effects

KW - Phosphoric Monoester Hydrolases/antagonists & inhibitors

KW - Pyrimidines/chemistry

KW - Pyrophosphatases/antagonists & inhibitors

KW - Reproducibility of Results

KW - Xenograft Model Antitumor Assays

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

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