According to a new study, led by the University of Eastern Finland, there is much more variation in cancer-causing KRAS mutations than originally believed.
Clinical trial abstract
The findings, which have been published in PLOS Computational Biology, have demonstrated that different mutations occurring in the same amino acid of the KRAS protein have significantly varied effects on protein function. This variance is so significant that the researchers believe different approaches may be required when trying to develop treatments and drugs.
Mutations that happen in the proteins in the human body are often linked to cancer development. The KRAS protein, whose mutations play a role in the development of pancreatic cancer, is considered an important one. Mutations of the glycine 12 amino acid of the KRAS protein can cause glycine to mutate into any of the six possible different amino acids, all of which make the protein overactive and consequently causes cancer development.
All six of these mutations were previously believed to be equal in their function, however, as this new study showed, this may not be the case and the different mutations may have a different effect on the protein.
In their analysis, the researchers evaluated the effect of the different mutations on protein function through computer-simulated molecular dynamics. This simulation revealed different effects and may partially explain why different mutations occur more or less frequently in different tissue types.
This is the first study to show that different mutations occurring in the same location have a different effect on the molecular-level function of the KRAS protein.
It is hoped that these findings will be able to improve the understanding of the effects of different mutations and in the future may help in the development and selection of drug therapy alternatives targeting the function of the mutated KRAS protein.
The study was conducted in collaboration between the University of Eastern Finland, Tampere University of Technology, the University of Tübingen in Germany and the University of Helsinki. A Finnish supercomputer administered by CSC – IT Centre for Science was used in the study. It was funded by the Academy of Finland and the EU.