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University of Dundee Researchers destroy ‘undruggable’ cancer-causing K-Ras protein

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The team has shown, for first time, that it is possible to target K-Ras for degradation using AdPROM system

Researchers at Scotland-based University of Dundee have demonstrated a new method of destroying 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 long been known to cause many cancers, including lung, colorectal and pancreatic cancers. But despite decades of work by researchers across the world, an inhibitor for this protein has proven elusive. As a result, scientists have increasingly looked to novel ways of targeting K-Ras.

A team from Dundee’s Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) led by Dr Gopal Sapkota, Programme Leader, Protein Phosphorylation, University of Dundee, had previously engineered the Affinity-directed PROtein Missile (AdPROM) system that allows for the efficient and rapid degradation of specific target proteins in cells. Being able to degrade intracellular disease-causing proteins offers a unique opportunity for therapeutic intervention but it was not known whether these ‘protein missiles’ would be able to destroy K-Ras.

In two papers, published this week in Cell Chemical Biology, the Dundee team has shown, for the first time, that it is possible to target K-Ras for degradation using the AdPROM system. 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 in this way 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 broad inhibitors of K-Ras with limited success. 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 so-called undruggable targets, which is something many believed K-Ras to be.”

Proteins, known as the building blocks of life, are vital to our existence and are found in every cell on Earth. They come in a huge variety of forms and perform a wide range of functions, including defending the body against diseases. In the vast majority of human diseases, amplification or genetic mutations alter the protein function in cells and this is what causes the damage that diseases wreak on the body.

K-Ras relays signals from outside the cell to the cell’s nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialised functions (differentiate). Cancer, in its simplest terms, is uncontrolled cell division, and certain mutations can cause the division process to go awry.

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 University’s Division of Signal Transduction Therapy (DSTT) collaboration, 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.

Dr Sapkota continued, “The AdPROM system provides a rapid way to test whether specific proteins are valid drug targets and informs rapidly whether protein destruction is a feasible drugging strategy. Now we know endogenous K-Ras proteins can be degraded, more resource-intensive efforts can be streamlined into developing small molecule degraders as drugs.

“Professor Dario Alessi, Director, MRC PPU, said, “The DSTT is our flagship collaboration between University of Dundee academic researchers and industry. This exciting collaboration has developed innovative methods to efficiently degrade K-Ras for the first time, opening the door for a new approach to treat cancers driven by the KRAS oncogene.”

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