Researchers from the Francis Crick Institute and Vividion Therapeutics have identified chemical compounds that can effectively block the cancer-related gene RAS from interacting with a crucial pathway tied to tumor development.
This promising treatment is set to progress into its first human clinical trial. If it proves to be safe and effective, it may offer a way to treat various cancers while reducing damage to healthy cells.
The RAS gene is vital for regulating how cells grow and divide, yet mutations occur in approximately 20% of cancers. When altered, RAS becomes persistently active, constantly signaling cells to grow and divide.
Inside each cell, RAS is located on the membrane, acting as an initiator in growth signaling networks. Completely inhibiting RAS or the enzymes it influences has been challenging because these pathways are necessary for normal cell functions. One such enzyme associated with RAS, known as PI3K, also plays a role in blood sugar regulation via insulin. Blocking PI3K entirely could lead to issues like hyperglycemia.
In their research published on October 9 in Science, the team employed a combination of chemical screening and biological tests to find compounds that interfere with the RAS-PI3K interaction, all while preserving normal cellular functions.
Vividion Therapeutics researchers identified a range of small molecules that bind to PI3K at the point where RAS usually attaches. Using an assay developed by the Crick team, they confirmed that these compounds effectively prevented RAS from binding to PI3K, yet allowed PI3K to maintain its other important roles, including those involved in insulin signaling.
The researchers then tested one of these compounds in mice with RAS-mutated lung tumors. The treatment inhibited tumor growth, and notably, there were no indications of heightened blood sugar levels.
Following that, they experimented with combining this new compound with one or two other drugs targeting enzymes within the same pathway. This combination yielded stronger and longer-lasting tumor suppression compared to using any single drug alone.
The scientists also evaluated the compound in mice bearing tumors with mutations in another cancer-associated gene, HER2, frequently overactive in breast cancer and linked to PI3K. The tumor growth was again curtailed, even though this response did not depend on RAS, hinting that the new compound might aid in combating a wider array of cancers.
Now, the drug has entered its initial clinical trial in humans to evaluate safety and potential side effects in individuals with RAS and HER2 mutations. The trial will also investigate whether the treatment is more effective when paired with other drugs targeting RAS.
Julian Downward, Principal Group Leader of the Oncogene Biology Laboratory at the Crick, noted: “The RAS gene is mutated across many cancers, and we’ve been focused on ways to prevent its interaction with cell growth pathways for years. However, side effects have been a significant barrier to treatment development.
“Our collaborative work has tackled this challenge by specifically targeting the interaction between PI3K and RAS, allowing PI3K to interact with its other targets. It’s exciting to see clinical trials get underway, demonstrating how a solid grasp of chemistry and basic biology can lead to potential solutions for cancer patients.”
“This discovery highlights how fresh approaches can pave the way for innovative cancer treatments,” stated Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion. “By creating molecules that block the RAS-PI3K connection while preserving healthy cellular processes, we’ve found a way to selectively inhibit a key cancer growth signal. It’s incredibly fulfilling to witness this science advancing in a clinical setting, where it may truly impact patients’ lives.”
