Dysfunctional redox regulation in cancer results in production of reactive oxygen species, damaging DNA and free deoxyribonucleotide triphosphates (dNTPs). The MTH1 protein, which is nonessential in normal cells, sanitizes oxidized dNTP pools, preventing incorporation of damaged bases during DNA replication in cancer cells.
As reported in Nature, Gad and colleagues found that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, which would result in DNA damage and cell death. First-in-class nudix hydrolase family small-molecule inhibitors (TH287 and TH588) were shown to potently and selectively engage and inhibit the MTH1 protein in vitro, with protein co-crystal structures showing that the agents bind in the active site of MTH1. The inhibitors caused incorporation of oxidized dNTPs in cancer cells, resulting in DNA damage, cytotoxicity, and antitumor response in patient-derived mouse xenografts.
The investigators concluded, “This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.” ■
Gad H, et al: Nature 508:215-221, 2014.