New clinical trial to target cancer’s elusive growth switch

(Press-News.org) Francis Crick Institute press release 

Under strict embargo: 19:00hrs BST Thursday 9th October 2025 

Peer reviewed  

Experimental study 

Animals  

Researchers at the Francis Crick Institute and Vividion Therapeutics have identified chemical compounds that can precisely block the interaction between the major cancer-driving gene RAS, and a key pathway for tumour growth.    

Now entering the first clinical trial in humans, if found to be safe and effective, these drugs could be used to treat many different types of cancers while avoiding effects on healthy cells.  

A gene called RAS, which kickstarts cell growth pathways, is mutated in around one in five cancers. Mutated versions of the gene lock the RAS protein in an activated state, telling the cancer cell to keep growing bigger and keep dividing.  

The RAS protein sits in the cell membrane and is the first ‘runner’ in a relay of cell growth. But completely blocking the activity of the RAS protein or the enzymes it controls can cause side effects, because these growth pathways are also important for healthy cells.  For example, an enzyme found to interact with RAS, called PI3K, also interacts with insulin to control sugar levels, so blocking it can cause hyperglycaemia.  

But in their work, published today in Science, the research team used a combination of chemical screening and biological experiments to find and test compounds that can block the interaction between RAS and PI3K without causing side effects on healthy cells.  

Scientists at Vividion Therapeutics identified a series of small compounds that irreversibly stick to the surface of PI3K near the RAS binding site, and then, using an assay developed by the Crick researchers, discovered that they prevented PI3K and RAS from binding, but still allowed PI3K to interact with other molecules, such as those in the insulin pathway.  

Researchers in the Oncogene Biology Laboratory at the Crick and the team at Vividion then tested one of these compounds in mice with RAS-mutated lung tumours, finding that the treatment halted tumour growth. Importantly, they also checked for and observed no evidence of hyperglycaemia. 

They then tested the new drug candidate in combination with one or two other drugs that also target enzymes in the RAS pathway. This combination resulted in stronger and longer-lasting tumour suppression compared to the individual treatments alone.   

Finally, the team also tested the drug candidate in mice with tumours containing mutations in another cancer-driving gene, HER2. This gene is often overexpressed in breast cancer, and the HER2 protein also interacts with PI3K. The researchers observed similar suppression of tumour growth, and surprisingly, this effect was independent of RAS, suggesting that the drug candidate may work to block the growth of even more types of tumours.  

The drug has now entered the first clinical trial in humans to test for safety and side effects in people with both RAS and HER2 mutations. The trial will also assess if the potential treatment is more effective in combination with other drugs targeting RAS.    

Julian Downward, Principal Group Leader of the Oncogene Biology Laboratory at the Crick, said: “Given the RAS gene is mutated across a wide range of cancers, we’ve been exploring how to stop it interacting with cell growth pathways for many years, but side effects have held back the development of treatments.  

“Our collaborative effort has overcome this challenge by targeting the PI3K and RAS interaction specifically, leaving PI3K free to bind with its other targets. It’s exciting to see these clinical trials starting, highlighting the power of understanding chemistry and fundamental biology to get to something with potential to help people with cancer.” 

“This discovery is a great example of how new discovery approaches can open up completely novel ways to tackle cancer,” said Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion. “By designing molecules that stop RAS and PI3K from connecting, while still allowing healthy cell processes to continue, we’ve found a way to selectively block a key cancer growth signal. It’s incredibly rewarding to see this science now progressing in the clinic, where it has the potential to make a real difference for patients.”  

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For further information, contact: press@crick.ac.uk or +44 (0)20 3796 5252  

Notes to Editors 

Reference: Klebba, J. et al. (2025). Covalent inhibitors of the PI3Ka RAS binding domain impair tumor growth driven by RAS and HER2. Science. 10.1126/science.adv2684. 

The Francis Crick Institute is a biomedical discovery institute with the mission of understanding the fundamental biology underlying health and disease. Its work helps improve our understanding of why disease develops which promotes discoveries into new ways to prevent, diagnose and treat disease. 

An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London. 

The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe. 

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