Pharmacologic MTH1 inhibition specifically induces cancer cell death and suppresses tumor growth.
Major finding: Pharmacologic MTH1 inhibition specifically induces cancer cell death and suppresses tumor growth.
Concept: MTH1 inhibitors induce misincorporation of oxidized nucleotides, causing lethal DNA damage.
Impact: Exploiting the altered redox state of cancer by MTH1 inhibition may be beneficial in diverse tumor types.
Overexpression of MutT homolog 1 (MTH1), which hydrolyzes the oxidized forms of dATP and dGTP to prevent misincorporation of damaged nucleotides into DNA, has been shown to prevent RAS-induced DNA damage and senescence and suppress the high mutation rate of mismatch repair–defective colorectal cancer cells. Because tumor cells typically exhibit elevated levels of reactive oxygen species (ROS), Gad and colleagues hypothesized that MTH1 might be essential for sanitizing the free nucleotide pool and preventing formation of lethal DNA damage in cancer cells. Indeed, siRNA-mediated depletion of MTH1 caused the accumulation of oxidized nucleotides in cancer cell DNA, induced DNA double- strand breaks and cancer cell apoptosis, and prevented xenograft tumor growth in vivo, but had no effect on normal cells. Selective small-molecule MTH1 inhibitors identified in a compound library screen phenocopied MTH1 knockdown and significantly blocked growth of a patient-derived xenograft model of chemoresistant melanoma. In another study, Huber and colleagues identified MTH1 as the target of SCH51344, a small molecule with selective cytotoxicity in RAS-transformed cells, and screened a library of clinically evaluated compounds for more potent MTH1 inhibitors. Surprisingly, the (S)-enantiomer of the MET/ALK inhibitor crizotinib potently inhibited MTH1 activity and blocked colony formation of RAS-mutant cancer cells. (S)-crizotinib treatment also induced the accumulation of oxidized nucleotides in DNA and significantly impaired xenograft tumor growth in vivo. Notably, both studies showed that MTH1 was overexpressed across a broad range of human cancers and that the cytotoxic effects of MTH1 inhibition were independent of RAS or p53 status, suggesting that MTH1 inhibitors might be active in diverse tumor types. Taken together, these studies identify an essential role for MTH1 as an adaptive mechanism to altered redox regulation in cancer cells and raise the possibility that MTH1 inhibitors might be selectively lethal to cancer cells due to nononcogene addiction to MTH1.
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