Control sites of ‘Death Star’ cancer protein identified

The allosteric control sites found in the so-called “Death Star” protein KRAS – one of the most frequently mutated genes in cancers – has been identified, scientists announced last night.

Researchers at the Centre for Genomic Regulation in Barcelona, Spain, and the Wellcome Sanger Institute, Cambridge, UK, say they are the first to complete a control map of proteins, showing secret vulnerabilities that can be exploited to control the effects of one of the most important causes of cancer.

The findings, published in Nature, provide vital insight into the protein that is found in one in 10 human cancers, with higher prevalence in deadly types such as pancreatic or lung cancers.

Since KRAS was first discovered in 1982, the only effective strategy to control it has been by targeting its allostery communication system, which are preferred for drug development as they offer greater specificity and reduce the likelihood of side effects. They can change a protein’s activity more subtly and they are generally safer and more effective compared to drugs targeting active sites.

However, allosteric sites are highly elusive and despite 40 years’ research, tens of thousands of scientific publications, and more than 300 published structures of KRAS, only two drugs – sotorasib and adagrasib – have been approved for clinical use.

In this study, the team mapped the allosteric sites by using deep mutational scanning, which involved creating more than 26,000 variations of the KRAS protein, changing only one or two amino acids at a time.

They checked how these different KRAS variations bind to six other proteins, including those critical for KRAS to cause cancer, and used artificial intelligence (AI) software to analyse the data, detect allostery and identify the location of known and new therapeutic target sites.

First author Chenchun Weng, postdoctoral researcher at the Centre for Genomic Regulation, said: “The unique selling point of our method is its scalability. In this work alone we made more than 22,000 biophysical measurements, a similar number as the total ever made for all proteins before we started harnessing the remarkable strides in DNA sequencing and synthesis methodologies. This is an enormous acceleration and demonstrates the power and potential of the approach.”

The technique revealed that KRAS has more strong allosteric sites than expected and mutations in these sites inhibited the protein’s binding to all three of its main partners. This, they say, suggests it is possible to inhibit KRAS activity of KRAS.

The authors add that a subset is particularly interesting because they are located in four different pockets that are easily accessible on the surface of the protein and could be promising targets for future drugs. One of these, “pocket 3”, is located far away from the active site of KRAS and previously received very little attention from pharmaceutical companies.

The team also found that making small alterations in KRAS can drastically change its behaviour with its partners, making the protein prefer one over another. This could lead to new strategies which control the aberrant activity of KRAS without hampering its normal function in non-cancerous tissues.

Senior study author Dr Ben Lehner, from the Centre for Genomic Regulation and the Wellcome Sanger Institute, said: “The big challenge in medicine isn’t knowing which proteins are causing diseases but not knowing how to control them.

“Our study represents a new strategy to target these proteins and speed up the development of drugs to control their activity. The nature of targeting allosteric sites means that the resulting drugs are likely to be safer, more effective treatments than the ones we have right now.”

Weng C et al. The energetic and allosteric landscape for KRAS inhibition. Nature 18 December 2023; doi: 10.1038/s41586-023-06954-0

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