Nature 508, 215–221 (2014)

Nature 508, 222–227 (2014)

Credit: NATURE

High levels of reactive oxygen species cause cellular damage in many ways, including oxidative damage to chemical components such as nucleotide triphosphate pools. However, cancer cells are quite resilient to this damage owing to the activity of the 7,8-dihydro-8-oxoguanine triphosphatase MTH1, which prevents incorporation of these oxidized nucleotides into DNA, avoiding genetic instability and cell death. Gad et al. and Huber et al. knocked down MTH1 expression in cancer cells and observed increased oxidized dNTP incorporation, DNA damage and apoptosis, whereas normal cells were unresponsive, suggesting that chemical inhibitors of MTH1 could be useful cancer therapeutics. Gad et al. screened compound libraries and identified two compounds, TH287 and TH588, which selectively bound the active site of MTH1, whereas Huber et al. identified MTH1 as the cellular target of the small molecule SCH51344, which blocked RAS-dependent anchorage. In addition, Huber et al. performed additional screening and identified the (S) enantiomer of the dual c-MET/ALK inhibitor crizotinib as an MTH1 inhibitor that exhibited improved pharmacokinetic properties and potency compared to SCH51344. In both studies, treatment of cancer cells and mouse tumor models with TH287, TH588 or (S)-crizotinib resembled MTH1 knockdown with an increase of oxidized dNTP incorporation into DNA, producing more DNA strand breaks and resulting in decreased tumor growth. Overall, these findings suggest an intriguing new approach to target cancer cells.