Researchers at the Francis Crick Institute and Vividion Therapeutics have achieved a significant breakthrough in cancer therapy by developing compounds that can precisely disrupt the interaction between the oncogenic RAS protein and the PI3K enzyme, a critical pathway for tumor growth. The lead compound has now entered Phase 1 clinical trials, representing a potential treatment for the approximately 20% of cancers driven by RAS mutations.
Targeting a Critical Cancer Pathway
The RAS gene, mutated in around one in five cancers, produces a protein that acts as a master regulator of cell proliferation. When mutated, RAS becomes locked in an activated state, continuously signaling cancer cells to grow and divide. The RAS protein initiates a relay of cell growth signals, with PI3K serving as a key downstream effector enzyme.
Previous attempts to target this pathway have been hampered by significant side effects. Complete blockade of PI3K activity causes hyperglycemia because the enzyme also plays essential roles in insulin signaling and glucose metabolism. This dual function has limited the therapeutic window of traditional PI3K inhibitors.
Selective Disruption Strategy
The research team, whose findings were published in Science, employed sophisticated chemical screening and biological experiments to identify compounds that could selectively interfere with the RAS-PI3K interaction without affecting other PI3K functions. Scientists at Vividion Therapeutics discovered small molecules that irreversibly bind to the PI3K surface near the RAS binding site.
Using a specialized assay developed by Crick researchers, the team confirmed that these compounds prevented RAS and PI3K from binding while allowing PI3K to maintain its interactions with other molecules, including those in the insulin pathway. This selectivity represents a major advancement in precision targeting of oncogenic signaling.
Preclinical Efficacy and Safety
In mouse models of RAS-mutated lung tumors, treatment with the lead compound resulted in complete halting of tumor growth. Importantly, researchers observed no evidence of hyperglycemia, addressing the primary safety concern associated with PI3K inhibition.
The team also tested combination therapies, pairing the new compound with one or two other drugs targeting different nodes in the RAS pathway. These combination treatments produced stronger and longer-lasting tumor suppression compared to individual treatments alone, suggesting potential for enhanced therapeutic efficacy through multi-modal approaches.
Broader Therapeutic Potential
In an unexpected finding, the compound also demonstrated efficacy against tumors driven by HER2 mutations, commonly found in breast cancer. Since HER2 also signals through PI3K but operates independently of RAS, this suggests the drug candidate may have utility across a wider spectrum of cancers than initially anticipated.
"The ability to selectively prevent RAS from binding PI3K while preserving other cellular functions exemplifies how nuanced targeting can unlock new treatment avenues," said Julian Downward, Principal Group Leader of the Oncogene Biology Laboratory at the Crick.
Clinical Development
The investigational compound has now entered first-in-human clinical trials designed to assess safety, tolerability, and preliminary efficacy in patients with tumors harboring RAS or HER2 mutations. The trial will also evaluate whether combining the drug with other RAS pathway inhibitors enhances therapeutic outcomes.
Matt Patricelli, Chief Scientific Officer at Vividion Therapeutics, emphasized the transformative potential of this approach: "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."
Implications for Cancer Treatment
This breakthrough represents a significant advancement in addressing one of oncology's most challenging targets. The selective disruption of pathogenic protein interactions, rather than complete enzyme inhibition, offers a new paradigm for cancer drug development that could maximize therapeutic benefit while minimizing treatment-limiting toxicities.
The collaboration between academic research and industry innovation demonstrates the power of combining fundamental biological insights with sophisticated chemical biology approaches to overcome long-standing barriers in drug discovery.
