Melanoma is the deadliest form of skin cancer and notorious for its resistance to conventional chemotherapy. Approximately 25 percent of melanoma is driven by oncogenic mutations in the NRAS gene, making it a very attractive therapeutic target. However, despite decades of research, no effective therapies targeting NRAS have been forthcoming.
For the first time, an international group of researchers has discovered a novel activator of NRAS and developed a specific inhibitor to effectively prevent NRAS mutant melanoma growth. These findings provide a promising therapeutic option to treat NRAS mutant melanoma.
The researchers first identified a novel serine/threonine kinase, STK19 (an enzyme encoded by the STK19 gene) to be a critical regulator of NRAS function. Then they characterized the mechanism by which this activation takes place through biochemical and cellular experiments.
STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19 D89N knockin leads to skin hyperpigmentation and promotes NRAS Q61R-driven melanomagenesis in vivo.
Finally, they designed an STK19 inhibitor (ZT-12-037-01) that efficiently prevented NRAS activation and development of NRAS mutant melanoma in an experimental model.
"This study provides a promising therapeutic strategy for melanoma treatment. Furthermore, the STK19 inhibitor might be a therapeutic option in 25 percent of all cancers with RAS mutations," explained corresponding author. "We hope our findings ultimately will be clinically translated into improved care for cancer patients."
A serine-threonine kinase regulates the skin cancer!
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