Breakthrough in cancer therapy targets key protein interaction to suppress tumors

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 tumor 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 tumors, finding that the treatment halted tumor 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 tumor suppression compared to the individual treatments alone. 

Finally, the team also tested the drug candidate in mice with tumors 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 tumor 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 tumors. 

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. 

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." 

Julian Downward, Principal Group Leader of the Oncogene Biology Laboratory at the Crick

"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."