Nucleotide metabolism: a pan-cancer metabolic dependency

Abstract

Overactive nucleotide synthesis is a hallmark of cancers and inhibitors of nucleotide synthesis pathways have shown promise in some cancer types. In this Review, Mullen and Singh give an overview of the role of aberrant nucleotide synthesis in supporting cancer cell growth, immune evasion, metastasis and resistance to cancer therapies, with a focus on identifying opportunities for the use of combination therapies to target these pathways more effectively. Metabolic alterations are a key hallmark of cancer cells, and the augmented synthesis and use of nucleotide triphosphates is a critical and universal metabolic dependency of cancer cells across different cancer types and genetic backgrounds. Many of the aggressive behaviours of cancer cells, including uncontrolled proliferation, chemotherapy resistance, immune evasion and metastasis, rely heavily on augmented nucleotide metabolism. Furthermore, most of the known oncogenic drivers upregulate nucleotide biosynthetic capacity, suggesting that this phenotype is a prerequisite for cancer initiation and progression. Despite the wealth of data demonstrating the efficacy of nucleotide synthesis inhibitors in preclinical cancer models and the well-established clinical use of these drugs in certain cancer settings, the full potential of these agents remains unrealized. In this Review, we discuss recent studies that have generated mechanistic insights into the diverse biological roles of hyperactive cancer cell nucleotide metabolism. We explore opportunities for combination therapies that are highlighted by these recent advances and detail key questions that remain to be answered, with the goal of informing urgently warranted future studies.