Science reports that scientists at the Francis Crick Institute and Vividion Therapeutics have discovered chemical agents that can specifically prevent the cancer‑driving protein RAS from binding to a key growth pathway enzyme, PI3K. This new approach promises to stop tumor growth while sparing healthy cells, enabling the first clinical trial in people.
A mutation in the RAS gene occurs in roughly one out of every five cancers. When altered, RAS remains permanently turned on, continuously telling the cancer cell to grow and divide. RAS is positioned on the cell membrane and initiates a cascade of proliferative signals. However, blocking all of RAS activity or its downstream enzymes can produce serious side effects, because these pathways are also essential for normal tissue function—for example, PI3K also regulates insulin and blood sugar control, and its inhibition can lead to hyperglycemia.
Using a combination of high‑throughput chemical screening and targeted biological assays, the team identified a series of small molecules that irreversibly attach to the surface of PI3K near the RAS binding pocket. In a custom assay developed by the Crick researchers, these compounds were shown to sterically block the PI3K–RAS interaction while leaving PI3K free to engage other partners, such as those in the insulin pathway.
In vivo studies using mice with RAS‑mutated lung tumours demonstrated that the most promising compound halted tumour growth. Importantly, the treatment did not induce elevated blood sugar levels. Subsequent experiments combined the drug with one or two other inhibitors that target enzymes in the RAS signalling network, yielding enhanced and sustained tumour suppression compared with each agent alone.
Further investigations revealed that the compound also suppressed tumour growth in mice bearing HER2‑mutated cancers. HER2, a gene frequently overexpressed in breast cancer, also interacts with PI3K. The observed tumour regression appeared independent of RAS, indicating that the new drug may effectively block growth signals in a broader range of malignancies.
Encouraged by these preclinical results, the researchers have initiated the first human clinical trial. The study will evaluate safety and tolerability in patients carrying RAS or HER2 mutations, and will also examine whether the drug works better in combination with existing RAS‑targeted therapies.
Julian Downward, Principal Group Leader of the Oncogene Biology Laboratory at the Crick: “The RAS gene is mutated across a wide spectrum of cancers, and we have long tried to inhibit its interaction with growth pathways while avoiding collateral damage to healthy cells. By targeting the PI3K‑RAS interface specifically, we keep PI3K free to perform its normal duties. It is exciting to see this strategy move into the clinic.”
Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion: “Our molecules block the RAS‑PI3K connection without shutting down other essential PI3K functions. This selective inhibition transforms a dangerous cancer signal into a treatable problem, and we are thrilled to bring this discovery from the bench to patients.”