Researchers discover method to 'turn off' mutated melanoma

(Boston)–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 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. Finally, they designed an STK19 inhibitor 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 Rutao Cui, MD, PhD, professor of pharmacology & experimental therapeutics at Boston University School of Medicine. “We hope our findings ultimately will be clinically translated into improved care for cancer patients.”

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Other corresponding authors include: Peng Wang, MD, PhD, Integrative Oncology, Fudan University Shanghai Cancer Center, (Shanghai, China) and Xianming Deng, PhD, State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, (Fujian, China).

These findings appear in the journal CELL.

This work was supported by grants from Boston University (to R.C.), the National Key R&D Program and the National Natural Science Foundation of China (No. 2017YFA0504504, 2016YFA0502001, 81422045, U1405223 and 81661138005 to X.D., 81622049 to P.W.), the Fundamental Research Funds for the Central Universities of China (No. 20720160064 to X.D.), the Program of Introducing Talents of Discipline to Universities (111 Project, B12001), and the Ludwig Institute for Cancer Research (to C.R.G).

Disclosure:

Chengqian Yin, Ting Zhang, Xianming Deng and Rutao Cui are co-inventors of a pending patent relating to this work. The other authors declare no competing interests.