Researchers have found that inhibiting the S6K2 gene could be an effective strategy for managing treatment-resistant melanoma, according to a recent study published by Lipchick et al in Science Translational Medicine.
Background
Cases of melanoma—the deadliest type of skin cancer—are currently rising. Since 2000, the number of melanoma cases per 100,000 U.S. individuals has increased from roughly 18 to 24, which may partially be the result of heightened exposure to ultraviolet radiation from sources such as spending time outdoors without protection from sunlight and using tanning beds.
NRAS-mutated melanoma accounts for about 30% of all melanoma cases. Previous research has indicated that mitogen-activated protein kinase (MAPK) inhibitors could serve as a potential therapy for this melanoma subtype; however, MAPK inhibitors are typically ineffective on their own in approximately 80% of cases and don’t extend patient survival.
Although cancer tends to be correlated with age, melanoma is one of the most common cancers diagnosed in patients aged younger than 30 years. Despite progress in treating melanoma, drug resistance remains a significant challenge, and many patients do not respond to current treatments.
Study Methods and Results
In the study, the researchers analyzed the downstream molecular and genetic impact of MAPK inhibition in treatment-resistant, NRAS-mutated melanoma
After assessing the data, the researchers revealed that expression of S6K2 was correlated with poorer outcomes and resistance to treatment with MAPK inhibitors in patients with NRAS-mutated melanoma. They then evaluated their hypothesis by silencing the S6K2 gene, which successfully killed NRAS-mutated melanoma cell lines known to resist MPAK inhibition. Further analysis revealed that S6K2 inhibition eliminated these cancer cells by disrupting a lipid metabolism process.
Further, the researchers discovered that silencing S6K2 had an effect on another gene called PPAR-alpha. After refining their understanding of PPAR-alpha’s effects on NRAS-mutated melanoma, they used a combination treatment comprising two compounds—fenofibrate, which activates PPAR-alpha, and DHA, also known as omega-3—to successfully induce cell death in melanomas that were known to resist treatment with MPAK inhibitors.
Conclusions
“Our findings suggest a clear path forward for more preclinical research on these treatment options,” suggested co–lead study author Brittany Lipchick, PhD, an associate staff scientist in the Villanueva Laboratory at Melanoma Research Center at The Wistar Institute. “Not only did our treatments work in the lab, they also appear to be quite safe. Some of the drugs we tested, like fenofibrate, are already safely used in humans for other purposes, so the road ahead is well-lit,” she added.
“Before this paper, we knew that certain treatments could theoretically work against melanomas that resist treatment with MAPK inhibitors, but they were a nonstarter, because they were incredibly toxic. 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,” highlighted co–lead study author Adam Guterres, PhD, an associate staff scientist at the Villanueva Laboratory at Melanoma Research Center at The Wistar Institute.
“This work shows that even in the face of notoriously treatment-resistant melanoma, targeting S6K2 is a viable strategy for improving therapeutic outcomes,” emphasized senior study author Jessie Villanueva, PhD, Associate Professor in the Ellen and Ronald Caplan Cancer Center at The Wistar Institute. “We’re excited to see where further research will lead us in the continued fight to reduce deaths from melanoma,” she concluded.
Disclosure: The research in this study was supported by the National Institutes of Health, the U.S. Department of Defense, the Pennsylvania Department of Health, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, The Melanoma Research Alliance, the V Foundation for Cancer Research, The Wistar Science Accelerator Award, and The Goldblum Family Healthcare Fund. For full disclosures of the study authors, visit science.org.
