Journal Article

MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Jacques-Cordonnier, Marie-Caroline, Almlöf, Ingrid, Homan, Evert J., Lundin, Cecilia, Eshtad, Saeed, Scobie, Martin, Svensson, Richard, Nilsson, Jonas A., Svensson, Linda M., Göktürk, Camilla, Axelsson, Hanna, Höglund, Andreas, Wallner, Olov A., Altun, Mikael, Baranczewski, Pawel, Jeppsson, Fredrik, Gustavsson, Anna-Lena, Wiita, Elisee, Häggblad, Maria, Martens, Ulf, Jemth, Ann-Sofie, Sanjiv, Kumar, Henriksson, Martin, Granelli, Ingrid, Schultz, Niklas, Kalderén, Christina, Johansson, Lars, Gad, Helge, Artursson, Per, Loseva, Olga, Gaugaz, Fabienne Z., Vikingsson, Svante, Berntsson, Ronnie P.-A., Helleday, Thomas, Jacques, Sylvain A., Saleh, Aljona, Johansson, Fredrik, Jensen, Annika Jenmalm, Strömberg, Kia, Olofsson, Roger, Hammarström, Lars G. J., Evers, Bastiaan, Koolmeister, Tobias, Lundbäck, Thomas, Pham, Therese, Desroses, Matthieu, Ström, Cecilia E., Gustafsson, Robert, Bräutigam, Lars, Hagenkort, Anna, Djureinovic, Tatjana, Puigvert, Jordi Carreras, Berglund, Ulrika Warpman, Einarsdottir, Berglind Osk, Lundgren, Bo, Stenmark, Pål, Vallin, Karl S. A.

2014

Overview

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. In order to find a general treatment for cancer, this study found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule inhibitors of MTH1, TH287 and TH588 — in the presence of these inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in patient-derived mouse xenograft models. MTH1 is Ras-linked target for cancer therapy Mutations in the Ras oncogene are associated with poor prognosis. It was known that overexpression of MTH1, a protein involved in preventing the incorporation of damaged bases into DNA, prevents Ras-induced senescence. In seeking to understand how damaged deoxynucleotides (dNTPs) promote cancer, Thomas Helleday and colleagues found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule MTH1 inhibitors, TH287 and TH588. In the presence of these hydrolase inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in mouse xenograft cancer models. In a second study, Giulio Superti-Furga and colleagues sought to identify the target of a small molecule, SCH51344, that had been developed for use against Ras -dependent cancers and found that it inactivates MTH1. This allowed them to identify a new potent inhibitor of MTH1 that is enantiomer-selective, ( S )-crizotinib. In the presence of this drug, tumour growth is suppressed in animal models of colon cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/2 / 13/31 / 13/89 / 14/19 / 38/47 / 631/337/1427 / 631/337/151 / 631/67/1059/602 / 64/60 / 82/83 / Animals / Apoptosis / Binding proteins / Biochemistry / biokemi / Cancer / Cancer and Oncology / Cancer cells / Cancer och onkologi / Cancer therapies / Catalytic Domain / Cell cycle / Cell Death - drug effects / Cell Survival - drug effects / Crystallization / Cytotoxicity / Defects / Deoxyguanine Nucleotides - metabolism / Deoxyribonucleic acid / Deoxyribonucleotides / DNA / DNA Damage / DNA Repair Enzymes - antagonists & inhibitors / DNA Repair Enzymes - chemistry / DNA Repair Enzymes - metabolism / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - pharmacokinetics / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Female / Genotype & phenotype / Humanities and Social Sciences / Humans / Inhibitors / Kinases / Male / MEDICIN / MEDICINE / Mice / Models, Molecular / Molecular Conformation / Molecular Targeted Therapy / multidisciplinary / Mutagenesis / Mutation / Neoplasms - drug therapy / Neoplasms - metabolism / Neoplasms - pathology / Nucleotides - metabolism / Nudix Hydrolases / Oxidation-Reduction - drug effects / Phosphoric Monoester Hydrolases - antagonists & inhibitors / Phosphoric Monoester Hydrolases - chemistry / Phosphoric Monoester Hydrolases - metabolism / Physiological aspects / Prevention / Proteins / Pyrimidines - chemistry / Pyrimidines - pharmacokinetics / Pyrimidines - pharmacology / Pyrimidines - therapeutic use / Pyrophosphatases - antagonists & inhibitors / Reproducibility of Results / Rodents / Science / Tumors / Xenograft Model Antitumor Assays