2. Academic Validation
  3. Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis

Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis

  • Cell. 2019 Feb 21;176(5):1113-1127.e16. doi: 10.1016/j.cell.2019.01.002.
Chengqian Yin 1,  Bo Zhu 1,  Ting Zhang 2,  Tongzheng Liu 3,  Shuyang Chen 1,  Yu Liu 4,  Xin Li 1,  Xiao Miao 5,  Shanshan Li 1,  Xia Mi 1,  Jie Zhang 6,  Li Li 2,  Guo Wei 7,  Zhi-Xiang Xu 8,  Xiumei Gao 9,  Canhua Huang 4,  Zhi Wei 6,  Colin R Goding 10,  Peng Wang 11,  Xianming Deng 12,  Rutao Cui 13
Affiliations

Affiliations

  • 1 Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
  • 2 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102 Fujian, China.
  • 3 Jinan University Institute of Tumor Pharmacology, Guangzhou, 510632 Guangdong, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu, 610041 Sichuan, China.
  • 5 Innovation Research Institute of traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 200000 Shanghai, China.
  • 6 Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102, USA.
  • 7 The Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
  • 8 Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35233, USA.
  • 9 Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 300193 Tianjin, China.
  • 10 Ludwig Institute for Cancer Research, University of Oxford, Headington, Oxford OX3 7DQ, UK.
  • 11 Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 200032 Shanghai, China. Electronic address: wangp413@163.com.
  • 12 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102 Fujian, China. Electronic address: xmdeng@xmu.edu.cn.
  • 13 Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: rutaocui@bu.edu.
PMID: 30712867 DOI: 10.1016/j.cell.2019.01.002
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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-122866
    98.67%, STK19 抑制剂
    Ras
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