Experimental RAS inhibitor shows promise for NRAS-driven melanoma

Melanoma kills more people than any other skin cancer, and for a quarter of patients whose tumors carry mutations in the NRAS gene, the treatment options narrow sharply once their first line of defense fails. Researchers at Huntsman Cancer Institute at the University of Utah believe they may have found a way through that bottleneck.

Martin McMahon and his team have been studying daraxonrasib, an experimental drug developed by Revolution Medicines that targets and disables RAS, a protein that drives cancer when mutated. The compound is not entirely new to the clinic. It recently earned a standing ovation from thousands of physicians at the American Society of Clinical Oncology Annual Meeting after demonstrating that it doubled survival time in patients with metastatic pancreatic cancer—a result so striking that Huntsman was one of only 60 hospitals worldwide selected to run that trial. Now McMahon's group has turned their attention to whether the same drug might work against melanoma driven by NRAS mutations.

In preclinical models—including actual tissue samples from melanoma patients—the results were striking. Mona Foth, the first author of the study published in Cancer Research, noted something unusual: the NRAS-driven tumors shrank in response to the drug. "It's actually quite rare that we see shrinkage of NRAS-driven tumors," she said. The finding matters because it addresses a real clinical gap. Most melanoma patients begin treatment with immunotherapy, which harnesses the body's own immune system to fight cancer. This approach has transformed care for advanced melanoma and works well for roughly half of all patients. But when immunotherapy fails or stops working—and it does for many—doctors have limited options. Patients with other melanoma mutations, like BRAF, can turn to approved targeted therapies. Those with NRAS mutations have essentially nothing.

"Patients with NRAS-driven melanoma do not have effective targeted therapies to treat their cancer," McMahon said. "Daraxonrasib is a targeted therapy that may provide another path for treatment and hope for patients affected by this devastating disease." The drug works by attacking the RAS protein directly, cutting off a pathway that cancer cells depend on to survive and multiply.

The research team did encounter a familiar problem: some of the tumor models developed resistance to the drug over time. They traced this resistance to mutations in MEK1, a protein that sits downstream of RAS in the cancer's signaling chain, or to the loss of cyclophilin A, a chaperone protein that daraxonrasib needs to do its job. This is not unexpected—resistance is a common challenge with pathway-targeted therapies—but it signals that the drug alone may not be the final answer. McMahon's team believes the next step is to identify combinations of drugs that could work together to prevent or overcome that resistance, deepening and extending the benefit for patients.

The path forward is clinical trials. McMahon and Foth are hoping to move daraxonrasib into human studies, starting with melanoma patients who either cannot tolerate immunotherapy or whose tumors have stopped responding to it. Neli Ulrich, the executive director of Huntsman's Comprehensive Cancer Center, noted that melanoma is particularly common in Utah and the Mountain West, making this work locally urgent as well as scientifically important. The research has been supported by the National Institutes of Health and the Huntsman Cancer Foundation. For now, the preclinical evidence suggests that a drug already showing promise in pancreatic cancer might open a door for melanoma patients who have run out of options.