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
  • 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: [email protected].
  • 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: [email protected].
  • 13. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: [email protected].
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.
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