Crystal structure of human MTH1 in complex with a key inhibitor.
Crystal structure of human MTH1 in complex with a key inhibitor.

In recent decades, the development of new anticancer agents has focused on targeting specific genetic defects in cancer cells. These are often effective initially, but are troubled with rapid resistance emerging. In the current study, the researchers present a general enzymatic activity that all cancers tested rely on and that seems to be independent of the genetic changes found in specific cancers. The research team shows that all the investigated cancer tumours need the MTH1 enzyme to survive. In this way, cancer cells differ from normal cells, which do not need this enzyme.

A new way of treating cancer

“The concept is built on the fact that cancer cells have an altered metabolism, resulting in oxidation of nucleotide building blocks. MTH1 sanitises the oxidized building blocks, preventing the oxidative stress from being incorporated into DNA and becoming DNA damage. This allows replication in cancer cells so they can divide and multiply. With an MTH1 inhibitor, the enzyme is blocked and damaged nucleotides enter DNA, causing damage and killing cancer cells. Normal cells do not need MTH1 as they have regulated metabolism preventing damage of nucleotide building blocks. Finding a general enzymatic activity required only for cancer cells to survive opens up a whole new way of treating cancer,” says Thomas Helleday, professor at Karolinska Institutet, who leads the study.

The structures determined at Stockholm University

“The research team at Stockholm University has determined the structure of human MTH1 in complex with molecules that inhibit the activity of MTH1. The detailed studies of how different molecules bind MTH1 has been essential in guiding the development of efficient inhibitors and will now be used to develop these inhibitors into drugs. We have previously solved the structure of MTH1 and studied how the enzyme recognizes and breaks down damaged nucleotide building blocks,” says Pål Stenmark, Associate Professor at the Department of Biochemistry and Biophysics, Stockholm University.

To take the treatment concept towards a clinical application, the scientists have taken a multidisciplinary collaboration strategy with researchers from five Swedish universities. They have produced a potent MTH1 inhibitor that selectively kills cancer cells in the tumours.

Ingrid Granelli, researcher at the Department of Analytical Chemistry, has, together with her research group, developed new bioanalytical methods for the inhibitors:

“The methods have been used to analyze the concentration of the new drugs and metabolite in mouse plasma. The determination of the concentrations gives us information on how the different inhibitors are taken up, distributed and broken down,” says Ingrid Granelli.

A video describing the structure of MTH1 and it interactions with the inhibitor TH588



However, a lot of work remains to be done before it is time for clinical trials, which are likely to take at least one or two years. In another article published in the same issue of Nature, parts of the Swedish research team, together with collaborators in Austria and the UK present results showing that even previously identified substances that kill cancer cells work by inhibiting the MTH1 enzyme, something which has not been known until now. That existing anticancer agents hit MTH1 shows that the concept really works.

About the project

The research team behind the results is concentrated at the Science for Life Laboratory (SciLifeLab), which on behalf of the Swedish Government recently set up a national research platform for drug development. The universities who participated in the partnership, in addition to Stockholm University and Karolinska Institutet, are Sahlgrenska Academy/University of Gothenburg, Uppsala University and Linköping University. The research was primarily funded by the Knut and Alice Wallenberg Foundation the Swedish Research Council and the Torsten Söderberg and Ragnar Söderberg Foundations.
Video about the project

Links to the articles in Nature

“MTH1 inhibition kills cancer by preventing sanitation of the dNTP pool”, Helge Gad, Tobias Koolmeister, Ann-Sofie Jemth et al., Nature, online 2 April 2014, doi: 10.1038/nature13181.

“Stereospecific targeting of MTH1 by (S)-crizotinib as anticancer strategy”, Kilian V. M. Huber, Eidarus Salah, Branka Radic et al., Nature, online 2 April 2014, doi: 10.1038/nature13194