'Achilles heel' of tumour cells discovered

A study conducted at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences shows that fast-growing cancer cells are sensitive towards imbalances in the metabolism of nucleotides, the building blocks of DNA - a vulnerability that can be exploited for a novel anti-tumour therapeutic approach.

The researchers, in collaboration with colleagues from the University of Oxford and Karolinska Institutet, identified the enzyme MTH1 as an Achilles heel of malignant tumour cells. They also discovered the chemical mirror image of an existing anticancer drug called crizotinib to be an efficient inhibitor of MTH1 activity. Their work has been published in the journal Nature.

The importance of MTH1 starts at replication forks, where DNA molecules are duplicated by template-guided serial assembly of nucleotide building blocks, which must be intact in order to prevent DNA damage and defects such as mutations. MTH1 is a nucleotide-sanitising enzyme that removes damaged nucleotides. Unlike in normal cells where this feature is not required because nucleotides are intact, cancer cells suffer from oxidative stress which leads to the damage of nucleotides.

MTH1 is thus indispensable for preserving genome integrity by preventing the incorporation of damaged DNA building blocks. Clearance of those building blocks damaged by oxidation allows cancer cells to divide and proliferate infinitely. Upon disruption of this protective mechanism by an MTH1 inhibitor, oxidised nucleotides are incorporated into newly synthesised DNA. The damaged DNA strands break and the cancer cell dies.

The CeMM researchers successfully applied a mass spectrometry-based analytical technique (chemical proteomics) to elucidate the mode of action of a small molecule that was found to selectively target cancer cells. When examining an incidentally impure laboratory-grade batch of the known and approved protein kinase inhibitor and anticancer drug crizotinib, they discovered an activity that could not be explained by the known properties of this compound.

Further investigations revealed that the impurity was the chemical mirror image (enantiomer) of crizotinib, which varies slightly in its three-dimensional structure - and is a highly specific inhibitor of the MTH1 enzyme. The researchers have demonstrated that MTH1-targeting drugs selectively induce DNA damage in cancer cells and impair growth of difficult-to-treat, aggressive human tumours in model systems.

“It’s really a rare stroke of luck that we have not only found a previously unknown sore spot of aggressive cancers, but that by chance we simultaneously identified a chemical substance that is a mirror image of one of the best new anticancer agents in the clinic,” said Giulio Superti-Furga, principal investigator and leader of the study.

Kilian Huber, first author of the study, said the chemical’s similarity to an already approved cancer drug “may open the opportunity to quickly test our findings in the clinic for the benefit of the patients”. However, it is likely that it will take one to two years before clinical trials are underway