Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis.
Yin C., Zhu B., Zhang T., Liu T., Chen S., Liu Y., Li X., Miao X., Li S., Mi X., Zhang J., Li L., Wei G., Xu Z-X., Gao X., Huang C., Wei Z., Goding CR., Wang P., Deng X., Cui R.
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.