Target System Shown to Attack K-Ras Protein

Researchers at the University of Dundee have shown that it is possible to destroy an ‘undruggable’ protein known to play a role in cancer, raising the possibility of a new therapeutic approach to the disease. Mutations of the K-Ras protein have caused cancers, including lung, colorectal and pancreatic cancers, but an effective inhibitor has proven elusive.

A team from Dundee’s School of Life Sciences, led by Dr Gopal Sapkota, approached this problem using its Affinity-directed PROtein Missile (AdPROM) system and have shown for the first time [1] that it is possible to target K-Ras for degradation. The use of this technology in humans remains some way off, but Dr Sapkota now expects rapid progress in chemical degraders of K-Ras over the next few years.

“K-Ras is the Holy Grail of cancer targets, so the knowledge that it can be targeted for degradation is an extremely promising discovery,” said Dr Sapkota. “This potentially allows for any small molecule that binds K-Ras, rather than just inhibitors which have proven to be elusive, to be converted into a degrader. In the next 10 years I would hope we have options available to target those cancers that are caused by K-Ras mutations.

“Many companies have tried to design inhibitors of K-Ras without much success, with just a single mutation-specific inhibitor having entered clinical trials so far. Instead we looked at whether it was possible to destroy the K-Ras protein using AdPROM. The idea that we can remove disease-causing proteins from the cell is very exciting, both in terms of research and drug discovery.

“Targeted destruction of disease-causing proteins is an exciting new approach to tackling the so-called undruggable targets, which is something many believed K-Ras to be.”

The AdPROM technology is relatively simple to assemble and can be used in any cell. The system uses small affinity probes, termed nanobodies or monobodies, which bind and recruit specific target proteins to the cells’ own protein degradation machinery.

The Sapkota lab, through the Division of Signal Transduction Therapy (DSTT) collaboration with funders GSK, used gene editing technology to tag the endogenous K-RAS gene with a Green Fluorescence Protein. By using the GFP-directed protein missile, they were able to rapidly and efficiently destroy tagged K-Ras proteins from these cells. The team then went on to use K-Ras directed protein missile and were able to destroy endogenous K-Ras as well. They will now work to develop selective binders of mutated K-Ras to achieve selective degradation of specific disease-causing mutations of this protein.

More information online

1. Published in Cell Chemical Biology