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

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 dNTPs. How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins are central regulators that coordinate nucleotide synthesis and ROS generation to drive the development of numerous human cancers. We herein performed a CRISPR-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven metabolic dependency. Mechanistically, MYC orchestrated the balance of two metabolic pathways that act in parallel, the NOX4-ROS pathway and the PLK1-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as the first-in-class degrader that potently and selectively depletes NUDT1 in vivo. Administration of LC-1-40 disrupted MYC-controlled metabolic homeostasis, resulting in excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.