Experimental Drug Blocks Development of Malignant Melanomas

Activating mutations in the NRAS (Neuroblastoma RAS viral oncogene homolog) gene account for 20%–30% of melanoma, but despite decades of research no effective anti-NRAS therapies have been developed.

With this in mind, investigators at Boston University School of Medicine (MA, USA) identified the previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. The protein encoded by STK19 localizes predominantly to the nucleus. Its specific function is unknown, but it is thought that phosphorylation of this protein may be involved in transcriptional regulation.

The investigators reported in the January 31, 2019, online edition of the journal Cell that STK19 phosphorylated NRAS, which enhanced its binding to its downstream effectors and promoted oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N (aspartate (D89) to aspargine) substitution in STK19 - whose alterations were identified in 25% of human melanomas - represented a gain-of-function mutation that interacted better with NRAS to enhance melanocyte transformation. STK19 D89N activation led to skin hyperpigmentation and promoted NRAS-driven melanoma formation in vivo.

In addition, the investigators described the development of the drug ZT-12-037-01 as a specific STK19-targeted inhibitor and showed that it effectively blocked oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo.

"This study provides a promising therapeutic strategy for melanoma treatment. Furthermore, the STK19 inhibitor might be a therapeutic option in 25% of all cancers with RAS mutations," said senior author Dr. Rutao Cui, professor of pharmacology and 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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