Mitotic MTH1 Inhibitorsin Treatment of Cancer.

Abstract

The DNA damage response (DDR) proteinMTH1 is sanitising the oxidized dNTP pool and preventing incorporation of oxidative damage into DNAand has an emerging role in mitosis. It is a stress-induced protein and often found to be overexpressed in cancer. MitoticMTH1 inhibitors arrest cells in mitosis andresult in incorporation of oxidative damage into DNA and selective killing of cancer cells. Here, I discuss the leading mitoticMTH1 inhibitor TH1579 (OXC-101, karonudib), now being evaluated in clinical trials, and describe its dual effect on mitosis and incorporation of oxidative DNA damage in cancer cells. I describe why MTH1 inhibitors that solely inhibits the enzyme activity fail to kill cancer cells and discuss if MTH1 is a valid target for cancer treatment. I discuss emerging roles of MTH1 in regulating tubulin polymerisation and mitosis and the necessity of developing the basic science insights along with translational efforts. I also give a perspective on how edgetic perturbation is making target validation difficult in the DDR field.