A new concept for the treatment of cancer
Crystal structure of human MTH1 in complex with a key inhibitor.
Source: Stockholm University, Prof. Pal Stenmark.
A team of researchers from five Swedish universities has identified a new way to treat cancer. They present their concept in the journal „Nature“. It is based on inhibiting a specific enzyme called MTH1. Cancer cells, unlike normal cells, need MTH1 to survive. Without this enzyme, oxidized nucleotides are incorporated into DNA, resulting in lethal DNA double-strand breaks in the cancer cells. The research group at Stockholm University has determined the structure of MTH1 based on diffraction measurements at HZB´s MX-beamline at BESSY II. These detailed structural studies are important for the development of efficient inhibitors targeting MTH1.
In recent decades, the development of new anticancer agents focused on targeting specific genetic defects in cancer cells. These often are effective initially, but later cause trouble due to emerging rapid resistance. 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 respect, cancer cells differ from normal cells, which do not need this enzyme.
“The concept is built on the fact that cancer cells have an altered metabolism, resulting in oxidation of nucleotide building blocks,” says Thomas Helleday, professor at Karolinska Institutet, who leads the study: "MTH1 repairs 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.
Original publication:
“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. http://dx.doi.org/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. http://dx.doi.org/10.1038/nature13194