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Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. 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<sup>D89N</sup> knockin leads to skin hyperpigmentation and promotes NRAS<sup>Q61R</sup>-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.

Original publication

DOI

10.1016/j.cell.2019.01.002

Type

Journal article

Journal

Cell

Publication Date

02/2019

Volume

176

Pages

1113 - 1127.e16

Addresses

Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.

Keywords

Cell Line, Tumor, Melanocytes, Animals, Mice, Inbred C57BL, Humans, Mice, Mice, Nude, Melanoma, Skin Neoplasms, Cell Transformation, Neoplastic, GTP Phosphohydrolases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins B-raf, Membrane Proteins, Nuclear Proteins, Signal Transduction, Phosphorylation, Mutation, Female, HEK293 Cells