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

Area of Science:

• Biochemistry
• Cancer Biology
• Metabolic Pathways

Background:

• Tumor cells exhibit high proliferation rates, necessitating significant nucleotide synthesis.
• Increased reactive oxygen species (ROS) production in cancer cells paradoxically damages DNA and deoxy-ribonucleoside triphosphates (dNTPs).
• The integration of nucleotide synthesis and ROS generation in tumorigenesis is not fully understood.

Purpose of the Study:

• To investigate the metabolic dependencies of MYC-driven cancers.
• To identify key enzymes involved in coordinating nucleotide metabolism and ROS generation.
• To explore NUDT1 as a potential therapeutic target in MYC-driven cancers.

Main Methods:

• A Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based functional screen was employed to target metabolic genes.
• Investigated the mechanistic link between MYC, NOX4-ROS pathway, and PLK1-NUDT1 pathway.
• Developed and tested a novel NUDT1 degrader, LC-1-40, in preclinical models.

Main Results:

• Nudix hydrolase 1 (NUDT1) was identified as a critical MYC-driven metabolic dependency.
• MYC was found to orchestrate a balance between the NOX4-ROS and PLK1-NUDT1 pathways.
• LC-1-40 effectively depleted NUDT1 in vivo, leading to excessive nucleotide oxidation and cytotoxicity.
• Therapeutic responses were observed in patient-derived xenografts treated with LC-1-40.

Conclusions:

• Targeting NUDT1 is a viable therapeutic strategy for MYC-driven cancers.
• Pharmacological inhibition of NUDT1 exploits a metabolic vulnerability in cancer cells.
• The interplay between ROS generation and nucleotide sanitization is crucial for cancer cell survival.