PHILADELPHIA, PA— Researchers at The Wistar Institute, led by Jessie Villanueva, Ph.D., have made significant strides in combating treatment-resistant melanoma. Their latest discovery focuses on inhibiting the gene S6K2, a breakthrough that has the potential to improve outcomes for patients with melanoma resistant to conventional treatments. The findings were published in Science Translational Medicine.
Melanoma, the deadliest form of skin cancer, remains a growing concern in the U.S. with cases rising from 18 to 24 per 100,000 Americans since 2000. Younger populations and those exposed to UV radiation face heightened risks, while resistance to existing therapies continues to hamper progress. For patients with NRAS-mutated melanoma, which represents 30% of cases, drug resistance is particularly problematic, as 80% of these patients do not respond to current MAPK inhibitor treatments.
The Villanueva lab’s research pinpointed the S6K2 gene as a key factor associated with poor patient outcomes and MAPK treatment resistance in NRAS-mutated melanoma. By silencing S6K2, researchers successfully killed melanoma cells previously resistant to MAPK inhibitors. This approach disrupts lipid metabolism, a critical process for cancer cell survival.
“This work shows that, even in the face of notoriously treatment-resistant melanoma, targeting S6K2 is a viable strategy for improving therapeutic outcomes,” said Dr. Villanueva, associate professor at Wistar’s Ellen and Ronald Caplan Cancer Center.
Furthering their efforts, the team explored combination treatments involving fenofibrate — a lipid-lowering drug that activates PPARα — and DHA, commonly known as Omega-3. Together, these compounds induced cell death in resistant melanoma cells without the significant toxicity seen with earlier potential therapies.
“Not only did our treatments work in the lab — they also appear to be quite safe,” said Brittany Lipchick, Ph.D., co-first author and associate staff scientist in the Villanueva lab. “Some of the drugs we tested, like fenofibrate, are already safely used in humans for other purposes, so the road ahead is well-lit.”
Adam Guterres, Ph.D., co-first author and associate staff scientist, noted the promising implications for patient care. “Our work shows that we can still fight this stubborn melanoma without a prohibitively toxic treatment, which is exciting news for where this work takes us.”
With this discovery, The Wistar Institute has opened a new avenue for preclinical research targeting melanoma drug resistance. The combination of targeted gene inhibition and safe, repurposed drugs holds the potential to advance melanoma therapies, offering hope for patients battling this relentless disease.
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