Abstract 4460: Targeting the redox-protective protein MTH1 for cancer therapy: A novel way to exploit the unique redox status of cancer cells

Abstract

Abstract Cancer cells are characterized by an increase in the rate of reactive oxygen species (ROS) production and an altered redox environment compared to normal cells. The role of ROS in tumorigenesis is two-fold. On the one hand, ROS play a causal role in tumor development and progression by inducing genomic instability and aberrant, pro-tumorigenic signalling. On the other hand, high levels of ROS can also be toxic to cancer cells, oxidizing and damaging both DNA and free nucleotides (dNTPs), which can lead to cell death. MutT Homolog 1 (MTH1) is a redox-protective phosphatase that converts ROS-oxidized nucleotides (8-oxo-dGTP) into their corresponding monophosphates, thus preventing their incorporation into genomic DNA and the resultant DNA damage and cell death. Recent studies have shown that MTH1 is up-regulated in various cancers and its activity is required for cancer cell survival and proliferation. Genetic knockdown of MTH1 and MTH1 small molecule inhibition led to DNA damage and cancer-specific cell death in vitro and in vivo, while having little effect on normal cells with a lower rate of ROS production. Hence, the unique redox status of cancer cells makes them reliant on redox-protective proteins like MTH1, which opens a novel therapeutic window to selectively induce cancer cell death via oxidative stress, while sparing normal cells. In order to validate MTH1 as a potential cancer therapeutic target, a wide range of cancer cells (lung, bone, colon, skin, and breast) were treated with a selective MTH1 inhibitor (TH588) or MTH1 shRNAs, and analysed for proliferation, cell survival, ROS levels and DNA damage. We found that MTH1 inhibition impaired cancer cell proliferation as well as anchorage-independent growth. Furthermore, TH588 induced cancer cell damage, as assessed by DNA damage markers and cancer cell death. Various normal, non-transformed cells (normal bronchial epithelial cells, normal lung fibroblasts and normal human epidermal melanocytes) were not affected by MTH1 inhibition. Antioxidants, which eliminate ROS, reversed the effects on cancer cells, indicating that ROS is the driver of cancer cell death and growth impairment upon MTH1 inhibition. Consequently, combination approaches using the MTH1 inhibitor together with pro-oxidants, further increased cancer cell susceptibility to oxidative stress. Based on our data, a MTH1 inhibitor may have clinical potential as a single agent or in combination with ROS inducers for the treatment of patients with various forms of cancer. Citation Format: Andrea Glasauer, Horst Irlbacher, Anja Richter, Luisella Toschi, Michael Steckel, Andrea Haegebarth. Targeting the redox-protective protein MTH1 for cancer therapy: A novel way to exploit the unique redox status of cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4460. doi:10.1158/1538-7445.AM2015-4460