Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma

Yalei Wen, Hui Wang, Xiao Yang, Yingjie Zhu, Mei Li, Xiuqing Ma, Lei Huang, Rui Wan, Caishi Zhang, Shengrong Li, Hongling Jia, Qin Guo, Xiaoyun Lu, Zhengqiu Li, Xiangchun Shen, Qiushi Zhang (), Lu Si (), Chengqian Yin () and Tongzheng Liu ()
Additional contact information
Yalei Wen: Jinan University
Hui Wang: Shenzhen Bay Laboratory
Xiao Yang: Jinan University
Yingjie Zhu: Jinan University
Mei Li: Jinan University
Xiuqing Ma: Jinan University
Lei Huang: Jinan University
Rui Wan: Jinan University
Caishi Zhang: Jinan University
Shengrong Li: Jinan University
Hongling Jia: Jinan University
Qin Guo: Shanxi Provincial People’s Hospital
Xiaoyun Lu: Jinan University
Zhengqiu Li: Jinan University
Xiangchun Shen: Guizhou Medical University
Qiushi Zhang: Jinan University
Lu Si: Peking University Cancer Hospital and Research Institute
Chengqian Yin: Shenzhen Bay Laboratory
Tongzheng Liu: Jinan University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Activating mutations in NRAS account for 15–20% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.

Date: 2024
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DOI: 10.1038/s41467-024-54140-1

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