Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis

Document Type

Article

Publication Date

2-21-2019

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. Pharmacological inhibition of the NRAS activator STK19 is a promising therapeutic option for the treatment of melanoma.

Identifier

85061833317 (Scopus)

Publication Title

Cell

External Full Text Location

https://doi.org/10.1016/j.cell.2019.01.002

e-ISSN

10974172

ISSN

00928674

PubMed ID

30712867

First Page

1113

Last Page

1127.e16

Issue

5

Volume

176

Grant

2016YFA0502001

Fund Ref

Boston University

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