Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis

Chengqian Yin, Bo Zhu, Ting Zhang, Tongzheng Liu, Shuyang Chen, Yu Liu, Xin Li, Xiao Miao, Shanshan Li, Xia Mi, Jie Zhang, Li Li, Guo Wei, Zhi xiang Xu, Xiumei Gao, Canhua Huang, Zhi Wei, Colin R. Goding, Peng Wang, Xianming DengRutao Cui

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1113-1127.e16
JournalCell
Volume176
Issue number5
DOIs
StatePublished - Feb 21 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • NRAS
  • RAS
  • STK19
  • cancer
  • drug screening
  • kinase inhibitor
  • melanoma
  • melanomagenesis
  • targeted cancer therapy

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