Revolutionary Breakthrough in the Battle Against Treatment-Resistant Melanoma

Dr. Villanueva, an associate professor at Wistar’s Ellen and Ronald Caplan Cancer Center, stated, “This research demonstrates that targeting S6K2 can be an effective strategy to enhance treatment outcomes, even for melanoma, which is notoriously resistant to therapies. We are eager to explore where this research may take us as we strive to decrease melanoma-related deaths.”

Melanoma is the most lethal type of skin cancer and is becoming increasingly common. Since the year 2000, melanoma cases among Americans have surged from approximately 18 to 24 per 100,000 people. Researchers believe this increase is partly due to heightened UV exposure from unprotected sun exposure or the use of tanning devices. While cancer is generally associated with older age groups, melanoma is particularly prevalent among individuals under 30, a demographic that is experiencing a rise in cases. Although there have been advancements in melanoma treatments, drug resistance continues to pose a significant challenge, leaving many patients unresponsive to existing therapies.

Within The Wistar Institute’s Melanoma Research Center, the Villanueva lab is focused on finding innovative methods to counter melanoma drug resistance. In their latest research, the team concentrated on melanomas bearing mutations in the NRAS gene (referred to as NRAS^MUT melanoma).

NRAS^MUT melanoma represents about 30% of melanoma cases, making it a major focus for researchers. Prior studies have suggested that MAPK inhibitors could serve as a potential treatment for this subtype, but they have failed in roughly 80% of cases, offering little improvement in patient survival on their own.

By investigating the downstream molecular and genetic consequences of MAPK inhibition in NRAS^MUT melanomas, the Villanueva team pinpointed the S6K2 gene as a target. Their analysis of melanoma patient data revealed that increased S6K2 expression was linked to poorer patient outcomes and resistance to MAPK treatment in those with NRAS^MUT melanoma.

The team experimentally tested their hypothesis by silencing the S6K2 gene in the lab, which effectively eliminated NRAS^MUT melanoma cell lines known for their resistance to MAPK inhibitors. Further investigation showed that disrupting S6K2 led to the death of these cancer cells by affecting a crucial lipid metabolism process.

The Villanueva lab’s findings on the potential of S6K2 inhibition against melanoma also unveiled another treatment strategy against MAPK-resistant melanomas. Upon silencing S6K2, the researchers observed an influence on another gene, PPARα. After investigating the effects of PPARα on NRAS^MUT melanomas, the team developed a combination treatment using fenofibrate (a PPARα activator) and DHA (Omega-3), successfully inducing cell death in melanomas that resisted MAPK inhibition.

Brittany Lipchick, Ph.D., a co-first author and associate staff scientist in the Villanueva lab, remarked, “Our results provide a clear direction for further preclinical research on these treatment possibilities. Not only were our lab treatments effective, but they also appear to be relatively safe. Some of the medications we explored, such as fenofibrate, are already safely administered to humans for various conditions, paving a promising path ahead.”

Adam Guterres, Ph.D., another co-first author and staff scientist in the Villanueva lab, reiterated, “Before this study, we understood that certain treatments might theoretically work against melanomas resistant to MAPK inhibitors, but they were largely dismissed due to their extreme toxicity. Our findings reveal that we can address this stubborn melanoma without resorting to highly toxic treatments, which is encouraging for future developments in this research.”