Abstract 105: MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells

Abstract

Abstract MTH1 prevents incorporation of oxidized deoxynucleoside triphosphates (e.g., 8-oxodGTP) into DNA. Earlier we demonstrated that MTH1 inhibitors TH588 and TH1579 possesses anti-cancer activity in various tumour types, while other structurally distinct MTH1 inhibitors failed to kill cancer cells or elevate the levels of oxidized nucleotides in DNA. In our current study, we found a novel function of MTH1 in mitosis, as it plays an important role in correct spindle assembly in cancer cells and progression through mitosis, and furthermore, we demonstrate MTH1 binds tubulin in vivo. We also observed that structurally distinct MTH1 inhibitors display differential abilities to break the MTH1 tubulin interaction, and also demonstrate that TH588 and TH1579 can directly inhibit tubulin polymerisation in vitro. Consistent with our results, we establish that TH588 and TH1579 kill cancer cells by a mitosis-dependent mechanism and implicate reactive oxygen species (ROS) accumulation and incorporation of oxidised nucleotides into DNA in this process. Furthermore, we found that non-cytotoxic MTH1 inhibitors can become cytotoxic and increase incorporation of oxidised nucleotides into DNA when they are combined with sub-therapeutic concentrations of mitotic inhibitors. In conclusion, MTH1 inhibitors killing cancer cells have a unique and complex mechanism of action: (1) causing a mitotic arrest, induced by targeting MTH1 which is required for mitotic progression, but also through direct inhibition of microtubule polymerisation, in-turn leading to an increase in ROS and likely 8-oxodGTP and (2) MTH1-dependent 8-oxodGTPase inhibitory activity causing incorporation of damaged nucleotides into DNA to kill cancer cells. Citation Format: Kumar Sanjiv, Helge gad, Sean G. Rudd, Oliver Mortusewicz, Ailine Stolz, Nuno Amaral, Lars Brautigham, Linda Pudelko, Christina Kaldéren, Ann-Sofie Jemth, Ingrid Almlöf, Torkild Visnes, Niklas Schultz, Johan Boström, José Manuel Calderon Montano1, Anna Hagenkort, Petra Groth, Camilla Gokturk, Tobias Koolmeister, Prasad Wakchaure, Evert Homan, Mikael Altun, Cecilia Ström, Martin Scobie, Holger Bastians, Ulrika Warpman Berglund, Thomas Helleday. MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 105.