@article{0be3aab2a1b04937a43161ea42bb049e,
title = "Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis",
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.",
keywords = "NRAS, RAS, STK19, cancer, drug screening, kinase inhibitor, melanoma, melanomagenesis, targeted cancer therapy",
author = "Chengqian Yin and Bo Zhu and Ting Zhang and Tongzheng Liu and Shuyang Chen and Yu Liu and Xin Li and Xiao Miao and Shanshan Li and Xia Mi and Jie Zhang and Li Li and Guo Wei and Xu, {Zhi xiang} and Xiumei Gao and Canhua Huang and Zhi Wei and Goding, {Colin R.} and Peng Wang and Xianming Deng and Rutao Cui",
note = "Funding Information: We thank Drs. Norman Sharpless and David Fisher for kindly providing the loxP-STOP-loxP NRAS Q61R knockin (LSL-NRAS Q61R ) mice. We thank Dr. Anurag Singh for kindly sharing cell lines. We also thank Drs. X. Shirley Liu, Tao Wang, Wantao Chen, Dali Liu, Chunxiao Xu, Jianming Zhang, and Junrong Zou for discussion and assistance. This work was supported by grants from Boston University (to R.C.), the National Key R&D Program , the National Natural Science Foundation of China ( 2017YFA0504504 , 2016YFA0502001 , 81422045 , U1405223 , 91853203 , and 81661138005 to X.D. and 81622049 to P.W.), the Fundamental Research Funds for the Central Universities of China ( 20720160064 to X.D.), the Program of Introducing Talents of Discipline to Universities ( 111 Project , B12001 ), and the Ludwig Institute for Cancer Research (to C.R.G.). Funding Information: We thank Drs. Norman Sharpless and David Fisher for kindly providing the loxP-STOP-loxP NRASQ61R knockin (LSL-NRASQ61R) mice. We thank Dr. Anurag Singh for kindly sharing cell lines. We also thank Drs. X. Shirley Liu, Tao Wang, Wantao Chen, Dali Liu, Chunxiao Xu, Jianming Zhang, and Junrong Zou for discussion and assistance. This work was supported by grants from Boston University (to R.C.), the National Key R&D Program, the National Natural Science Foundation of China (2017YFA0504504, 2016YFA0502001, 81422045, U1405223, 91853203, and 81661138005 to X.D. and 81622049 to P.W.), the Fundamental Research Funds for the Central Universities of China (20720160064 to X.D.), the Program of Introducing Talents of Discipline to Universities (111 Project, B12001), and the Ludwig Institute for Cancer Research (to C.R.G.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = feb,
day = "21",
doi = "10.1016/j.cell.2019.01.002",
language = "English (US)",
volume = "176",
pages = "1113--1127.e16",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}