In vivo validation of MTH1 as an anticancer target
DNA damaging agents, i.e., radio- and chemotherapy, constitute the backbone for treatment of a wide variety of cancers and may result in a complete cure from the disease. Emerging data demonstrates that cancer cells harbour high level of endogenous DNA damage caused by replication, oxidative and other DNA damage stress.
Consequently, cancer cells may require a specific DNA repair pathway to mediate survival to the high load of endogenous DNA damage. Cancers have deregulated levels of reactive oxygen species (ROS), damaging both DNA and free dNTPs. The MTH1 protein sanitises oxidized dNTP pools, converting 8-oxo-dGTP to 8-oxo-dGMP, to prevent incorporation of damaged bases during DNA replication. MTH1 overexpression reverses the mutator phenotype caused by mismatch repair defects and prevents Ras-induced senescence by suppressing the overall level of DNA damage.
This data suggest that a majority of the damage in cancer cells occurs on the free dNTP pool and that this needs sanitation for cancer cell survival. Here we show that cancer cells are dependent on MTH1 activity for survival, due to the effects of MTH1 in preventing incorporation of oxidized dNTPs into DNA to avoid ATM and p53 mediated apoptosis. As MTH1-/- mice are viable and MTH1 is not required for survival of non-transformed cells, targeting MTH1 may selectively cause DNA damage to cancer cells.
We validate MTH1 as an anti-cancer target in vivo and describe small molecules, TH287 and TH588 that potently and selectively inhibit MTH1. Protein co-crystal structures demonstrate that the compounds bind as inhibitors in the enzymatic pocket of MTH1. These first-in-class inhibitors of the Nudix hydrolase family cause increased incorporation of oxidized dNTPs in cells subject to high ROS levels, causing DNA damage and cytotoxicity to cancer cells. This study exemplifies a new general therapeutic approach to convert oxidative stress to cytotoxic DNA damage and cancer cell death.
Presented by
Thomas Helleday,
Professor
Professor Thomas Helleday received his PhD in Genetic Toxicology and a separate BSc in Business Administration and Economics from Stockholm University, Sweden. In 2000, he started an independent research group at the Institute for Cancer Studies, University of Sheffield, UK. The group was first to demonstrate a novel concept for treating cancer, targeting BRCA mutated breast and ovarian cancers with PARP inhibitors using the concept of synthetic lethality.
At the age of 35 years old, he received his third professorship at University of Oxford and a chair in cancer therapeutics, within the Gray Cancer Research UK Institute. Professor Helleday has been awarded numerous eminent international grants, prizes and awards in recognition of his research accomplishments including the Eppendorf-Nature Young European Investigator Award (2005) for outstanding contribution within the field of biomedical science by the journal Nature and the prestigious ERC advanced grant.
Professor Helleday was recruited to Karolinska Institutet/SciLifeLab on the Jubilee Professorship donated by the Torsten and Ragnar Söderberg Foundation and jointly appointed as strategic Professor in Chemical Biology. He currently heads the Division of Translational Medicine and Chemical Biology at Karolinska Institutet, SciLifeLab. The research covers both basic and translational work including academic-driven clinical trials, based on basic science findings in his laboratory.
