Scientists from the Francis Crick Institute and Vividion Therapeutics have developed chemical compounds that prevent the RAS gene from signaling tumor growth via the PI3K pathway. The treatment stopped tumor growth in mice models of lung and breast cancer without causing side effects like hyperglycemia. It is now entering human clinical trials.
The RAS gene, mutated in about one in five cancers, drives uncontrolled cell growth by constantly activating pathways like PI3K, which is also vital for normal functions such as insulin signaling. Blocking these pathways entirely has led to issues like elevated blood sugar in past attempts.
In a study published on October 9 in Science, researchers identified small molecules that covalently bind to PI3K's surface, blocking its interaction with RAS while preserving other PI3K roles. Tests in mice with RAS-mutated lung tumors showed the compound halted growth without raising blood sugar levels.
Combining the compound with one or two other drugs targeting the same pathway enhanced tumor suppression, lasting longer than single-drug treatments. It also worked against HER2-mutated tumors, common in breast cancer, by similarly disrupting PI3K interactions, suggesting broader applications.
The treatment is now in its first human trial, assessing safety in patients with RAS and HER2 mutations and potential benefits when combined with other RAS-targeting drugs.
Julian Downward, Principal Group Leader at the Crick's Oncogene Biology Laboratory, stated: "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."
Matt Patricelli, Chief Scientific Officer at Vividion Therapeutics, added: "This discovery is a great example of how new discovery approaches can open up completely novel ways to tackle cancer. 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."