Scientists discover new weapon in the fight against skin cancer

Melanoma is the deadliest form of skin cancer, and cases are rising. Since 2000, diagnoses in the U.S. have increased from 18 to 24 per 100,000 people.

Scientists attribute this rise partly to increased exposure to ultraviolet (UV) radiation from the sun and tanning beds. Unlike most cancers, which predominantly affect older individuals, melanoma is also common in people under 30. Despite significant progress in treatment, many patients experience resistance to available therapies, making new approaches crucial.

A team at The Wistar Institute’s Melanoma Research Center, led by Dr. Jessie Villanueva, has identified a promising strategy for attacking melanoma resistant to standard treatments.

Their study, published in Science Translational Medicine, explores how inhibiting the gene S6K2 could enhance treatment for patients whose tumors no longer respond to current therapies.

Melanomas with mutations in the NRAS gene, known as NRASMUT melanomas, account for nearly 30% of all cases. These tumors are particularly aggressive and often resist therapy.

Current treatments target the mitogen-activated protein kinase (MAPK) pathway, a key driver of melanoma growth. However, MAPK inhibitors only work in about 20% of cases and do not significantly improve survival rates.

When the MAPK pathway is blocked, the cancer cells activate an alternative survival route, the phosphoinositide 3-kinase (PI3K) pathway. Attempts to block both pathways simultaneously have been unsuccessful, as the necessary drug combinations are too toxic for patients to tolerate.

Researchers suspected that instead of targeting both pathways, focusing on a shared downstream node could offer a safer alternative. By mapping the molecular network activated by NRAS mutations, they found a critical player: the S6K2 gene.

The Wistar team discovered that NRASMUT melanoma cells rely on S6K2 for survival, particularly when MAPK inhibitors fail. By silencing this gene in laboratory models, researchers were able to kill resistant melanoma cells.

Further analysis revealed that S6K2 plays a crucial role in maintaining lipid metabolism—a process that cancer cells manipulate to fuel their uncontrolled growth. When S6K2 was inhibited, the cells lost their ability to regulate lipids properly, triggering a fatal chain reaction of metabolic stress and oxidative cell death.

“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. “We’re excited to see where further research will lead us in the continued fight to reduce deaths from melanoma.”

Further investigation led researchers to another discovery. The team found that S6K2 interacts with another gene called PPARα, which is involved in lipid metabolism. When S6K2 was silenced, PPARα became dysregulated, worsening the metabolic imbalance in the cancer cells.

By leveraging this knowledge, the researchers tested a combination therapy using fenofibrate, a drug that activates PPARα and is already approved for treating high cholesterol, along with DHA, an omega-3 fatty acid.

The results were promising—this combination successfully induced cell death in MAPK inhibitor-resistant melanoma cells without the severe toxicity seen with previous treatments.

The discovery that an existing cholesterol-lowering drug could be repurposed for melanoma offers a practical path forward. Because fenofibrate is already approved for human use, researchers hope to accelerate its clinical application for melanoma treatment.

“Our findings suggest a clear path forward for more preclinical research on these treatment options,” said Dr. Brittany Lipchick, co-first author and associate staff scientist in the Villanueva lab. “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.”

The challenge of treating melanoma has always been its ability to adapt and resist therapy. However, this study provides new hope. By targeting metabolic vulnerabilities unique to cancer cells, the approach offers a way to selectively kill resistant melanoma without harming normal cells.

Co-first author Dr. Adam Guterres highlighted the significance of this breakthrough: “Before this paper, we knew that certain treatments could theoretically work against melanomas that resist treatment with MAPK inhibitors, but they were a non-starter 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.”

With these promising results, the next step is to conduct further preclinical studies and eventually clinical trials. If successful, this strategy could lead to more effective treatments for melanoma patients who currently have limited options.

The findings from this study add to a growing body of research focused on finding safer, more effective ways to treat aggressive melanoma. The combination of S6K2 inhibition and metabolic therapy could change how NRASMUT melanoma is treated, offering new hope to patients facing resistance to existing drugs.

By identifying a novel approach that avoids the toxicity issues of previous combination therapies, the Wistar Institute team has provided a new direction for melanoma research.

As further studies refine these findings, the hope is that these discoveries will translate into life-saving treatments for melanoma patients worldwide.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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