Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis

Posted: 2019-02-07   Visits: 345

Abstract: 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. STK19D89N knockin  leads to skin hyperpigmentation and promotes NRASQ61R-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.


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