The RAS gene is crucial for regulating cell growth and division, but mutations in it are found in about one in five cancers. When altered, RAS becomes locked in an “on” state, constantly sending growth signals that drive uncontrolled cell proliferation.
The compounds are now moving into their first human clinical trial, a critical step toward transforming this lab breakthrough into a viable cancer therapy.
Within the cell, RAS is positioned on the membrane, where it triggers a cascade of signals that control growth. However, fully disabling RAS or the enzymes it influences has been challenging, since these same pathways are vital for normal cell activity. One of these enzymes, known as PI3K, also plays a key role in regulating blood sugar through insulin, meaning that completely blocking it can cause side effects like hyperglycemia.
Published on October 9 in Science, the study details how the team used chemical screening alongside biological testing to pinpoint compounds that block the interaction between RAS and PI3K while preserving normal cellular activity.
Using a combination of advanced chemical screening and biological assays, researchers identified a novel strategy, stop RAS and PI3K from connecting, while leaving PI3K’s normal functions intact.The researchers then tested the new compound in combination with one or two additional drugs targeting enzymes in the same pathway. This multi-drug approach produced stronger and more durable tumor suppression than any single drug alone.The team also tested the compound in mice with tumors fueled by HER2 mutations, a gene commonly overactive in breast cancer that also engages with PI3K. Impressively, tumor growth was stopped even without involving RAS, indicating the compound may be effective against a broader spectrum of cancers.
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.
Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion, 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.”