Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability

Minhui Ye, Yingzhe Fang, Lu Chen, Zemin Song, Qing Bao, Fei Wang, Hao Huang, Jin Xu, Ziwen Wang, Ruijing Xiao, Meng Han, Song Gao, Hudan Liu, Baishan Jiang () and Guoliang Qing ()
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Minhui Ye: Wuhan University
Yingzhe Fang: Wuhan University
Lu Chen: Wuhan University
Zemin Song: Wuhan University
Qing Bao: Wuhan University
Fei Wang: ShanghaiTech University
Hao Huang: Wuhan University
Jin Xu: Wuhan University
Ziwen Wang: Sun Yat-sen University Cancer Center
Ruijing Xiao: Wuhan University
Meng Han: Tsinghua University Technology Center for Protein Research
Song Gao: Sun Yat-sen University Cancer Center
Hudan Liu: Wuhan University
Baishan Jiang: Wuhan University
Guoliang Qing: Wuhan University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free deoxy-ribonucleoside triphosphates (dNTPs). How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins coordinate nucleotide synthesis and ROS generation to drive the development of numerous cancers. We herein perform a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven dependency. Mechanistically, MYC orchestrates the balance of two metabolic pathways that act in parallel, the NADPH oxidase 4 (NOX4)-ROS pathway and the Polo like kinase 1 (PLK1)-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as a potent, on-target degrader that depletes NUDT1 in vivo. Administration of LC-1-40 elicits excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.

Date: 2024
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DOI: 10.1038/s41467-024-46572-6

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