Novel inhibitor targets RAS-driven cancers

Targeted cancer therapy is designed to attack cancer cells with precision. It is widely used to treat tumors such as colorectal, breast, pancreatic and ovarian cancers. One of the most common drivers of many human cancers is activation of the RAS oncoprotein, a protein encoded by cancer-causing genes known as oncogenes. Previous studies have shown that directly targeting RAS for cancer treatment has long been challenging because of limitations in the protein’s structure and function.

Illustration of the activation process of a Ras protein. Inactive Ras protein (left) is activated by a guanine nucleotide exchange factor protein, opening the binding site and allowing guanosine diphosphate to exit. Afterwards, guanosine triphosphate can bind to RAS, turning it into the active form (right).

In a recent study published in the Journal of Biological Chemistry, scientists from the University of Louisville and the University of Cincinnati College of Medicine discovered a small-molecule inhibitor called C4-180 that targets a previously unexplored but critical cancer signaling route activated by RAS mutations.

The authors said the discovery could lead to therapies for a broad range of tumors.

The new molecule C4-180 directly targets cancer-activating regions of RALGEF, or Ral guanine nucleotide exchange factors, a signaling network downstream of RAS proteins. Computational studies showed that C4-180 fits into the RALGEF region and binds to it. This binding disrupts cancer signaling without interfering with other cellular processes. In laboratory studies, this molecule suppressed pancreatic tumor growth.

Another variant of the drug, called C4, reduced lung cancer metastasis without detectable toxic effects. Metastasis occurs when cancer from one region spreads to a secondary region within the human body.

Commercially available RAS inhibitors that target the first two pathways have limited effectiveness because patients often develop drug resistance. Moreover, combination treatments involving multiple drugs have caused toxicity in patients, an effect that was not observed with C4 variants.

“The low toxicity observed suggests that the agent is a good candidate for future combination therapy with a variety of standard-of-care approaches,” Geoffrey J. Clark, study corresponding author, said.

He added that, for the drug to reach clinical trials, it must first be optimized to ensure proper delivery to the target tissues and cells.

Overall, drug solubility and sex-based differences in tumor response were identified as key areas for future research.

C4-180 is the first small-molecule drug shown to bind directly to the RALGEF pathway and demonstrate antitumor activity in the body. The authors suggest combining C4-180 with other inhibitors to limit drug resistance and more fully suppress cancer-driving pathways.

The discovery, particularly when paired with other therapies, could significantly advance cancer research and treatment.