Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition

Abstract

Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity.Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1a response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance. Cancer Res; 76(8); 2366-75. Ó2016 AACR.

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

“…We thus suggest that the improved survival in response to TH588 and TH1579 treatment in cells, where the spindle assembly checkpoint is disturbed, can be explained by less time spent in mitosis, ultimately resulting in lower levels of ROS generation and reduced accumulation of toxic 8-oxodG in DNA. Previously, both we and others have demonstrated that cell death caused by TH588 treatment is associated with ROS formation, supporting this hypothesis[25,26]. Hence, MTH1i of 8-oxodGTPase only becomes relevant in presence of ROS in mitotically arrested cells.…”

The Epstein–Barr virus nuclear antigen-1 upregulates the cellular antioxidant defense to enable B-cell growth transformation and immortalization

“…The different behavior of the cell lines used in our assays point to the possibility that at least some of these failures may be explained by the type of cells used in the assays, where variations in the multifactorial control of the oxidative balance and the cell intrinsic capacity to detect and respond to oxidative DNA damage may determine the degree of dependency on MTH1. Overall, our findings corroborate previous observations linking the potency of MTH1 inhibitors to the extent of oxidative stress [35,36], suggesting that the endogenous levels of ROS could provide a useful biomarker of sensitivity.…”

MTH1 inhibitor TH588 induces mitosis-dependent accumulation of genomic 8-oxodG and disturbs mitotic progression

“…The cytotoxic effects of TH588 have been proposed to be independent of targeting MTH1 and independent of 8-oxodGTP (9,10,17), while we have shown TH588 cytotoxicity is related to ROS and partly rescued by expression of the bacterial 8-oxodGTPase MutT (6,12,18). Here, we wanted to use this experimental system to determine the contribution of 8-oxodGTP incorporation to the cytotoxicity of TH588.…”