2. Academic Validation
  3. Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability

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

  • Nat Commun. 2024 Mar 16;15(1):2377. doi: 10.1038/s41467-024-46572-6.
Minhui Ye # 1 2,  Yingzhe Fang # 1 2,  Lu Chen 2,  Zemin Song 3,  Qing Bao 2,  Fei Wang 4,  Hao Huang 2,  Jin Xu 2,  Ziwen Wang 5,  Ruijing Xiao 3,  Meng Han 6,  Song Gao 5,  Hudan Liu 2,  Baishan Jiang 7,  Guoliang Qing 8 9 10
Affiliations

Affiliations

  • 1 Department of Urology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
  • 2 Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
  • 3 TaiKang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 6 Protein Chemistry and Proteomics Facility, Tsinghua University Technology Center for Protein Research, Beijing, 10084, China.
  • 7 Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430071, China. [email protected].
  • 8 Department of Urology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China. [email protected].
  • 9 Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430071, China. [email protected].
  • 10 TaiKang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China. [email protected].
  • # Contributed equally.
PMID: 38493213 DOI: 10.1038/s41467-024-46572-6
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.

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