MTH1 as a Chemotherapeutic Target: The Elephant in the Room

Abstract

Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated ROS levels, many tumors develop adaptive responses, such as enhanced redox-protective or oxidatively-generated damage repair pathways. Targeting these enhanced oxidative stress-protective mechanisms is likely to be both therapeutically effective and highly specific to cancer, as normal cells are less reliant on such mechanisms. In this review, we discuss one such stress-protective protein human MutT Homolog1 (MTH1), an enzyme that eliminates 8-oxo-7,8-dihydro-2'-deoxyguanosine triphosphate (8-oxodGTP) through its pyrophosphatase activity, and is found to be elevated in many cancers. Our studies, and subsequently those of others, identified MTH1 inhibition as an effective tumor-suppressive strategy. However, recent studies with the first wave of MTH1 inhibitors have produced conflicting results regarding their cytotoxicity in cancer cells and have led to questions regarding the validity of MTH1 as a chemotherapeutic target. To address the proverbial "elephant in the room" as to whether MTH1 is a bona fide chemotherapeutic target, we provide an overview of MTH1 function in the context of tumor biology, summarize the current literature on MTH1 inhibitors, and discuss the molecular contexts likely required for its efficacy as a therapeutic target.

Keywords: MTH1; MTH1 inhibitors; RAS oncogene; cancer; nucleotide pool; oxidative stress; p53; therapeutic target.

Figure 1

Effect of elevated MTH1 mRNA levels on disease-free survival in RAS-driven cancers. Data and statistics were obtained from the cBioportal website for the indicated TCGA provisional datasets. The percentage of the total samples in which MTH1 (NUDT1) gene is amplified or mRNA is upregulated is shown below the survival curves. (A) Lung adenocarcinoma dataset. Kaplan-Meier curve data represent 221 cases. Median months disease-free (NUDT1 unaltered) = 44.02, median months disease-free (NUDT1 elevated) = 25.33; (B) Pancreatic adenocarcinoma dataset. Kaplan-Meier curve data represent 141 cases. Median months disease-free (NUDT1 unaltered) = 17.12, median months disease-free (NUDT1 elevated) = 6.93.

Figure 2

The elephant in the room. Schematic summarizing the molecular and cellular contexts that likely affect MTH1 inhibition-associated outcomes.