Nucleotide metabolism: a pan-cancer metabolic dependency

Abstract

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.

Molecular determinants of immunogenic cell death elicited by radiation therapy

“…Similarly, ATG5‐deficient CT26 tumors growing in immunocompetent BALB/c mice partially lose their ability to respond to ICD‐inducing chemotherapeutics such as mitoxantrone, 26 as well as to RT (delivered as a single dose of 8 Gy), 106 two therapeutic approaches that been shown to trigger ATP release from various human and murine cancer cell lines in vitro and/or in vivo 26,64,87 . Importantly, such a defect could be rescued by the concomitant administration of a CD39 inhibitor, suggesting it indeed reflected limited ATP release downstream of defective autophagy 106,107 . Further corroborating the importance of this pathway for ICD as driven by RT, systemic autophagy activation by alternate‐day feeding or caloric restriction, 108–112 has been shown to considerably improve the ability of a single RT dose of 6–8 Gy to limit local disease progression and metastatic dissemination of mouse TNBC 4T1 and 67NR lesions established in immunocompetent BALB/c mice 113,114 .…”

Purine and purinergic receptors in health and disease

“…Once entering the extracellular space, nucleotides such as ATP will be degraded by different extracellular nucleotidases into corresponding nucleosides 24 . For instance, nucleoside triphosphate dephosphorylase (CD39) can convert ATP or adenosine diphosphate (ADP) into adenosine monophosphate (AMP), while ecto‐5′‐nucleotidase (CD73) further converts AMP into adenosine 25 . The abnormal metabolism of extracellular ATP (eATP) not only represents a timely response to various cellular stressors such as inflammation and tissue damage, 26 but also exerts critical effects on the development and immune regulation of the TME 27,28 …”

Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy

“…Significantly, nucleotides and their metabolites from cancer cells can promote or inhibit antitumor immune responses by activating several receptors. The accumulation of extracellular ATP (eATP), a strong pro-inflammatory signal, can cause extensive antitumor immune responses by activating Toll-like receptors (TLRs) . However, eATP can be metabolized to immunosuppressive adenosine in the presence of ectonucleotidases CD39 (NTPDase 1) and CD73 (5′-NT) in TME. , The binding of adenosine to its receptors (e.g., A1, A2A, A2B, and A3) promotes the development of tumor-infiltrating immunosuppressive cells while undermining the infiltration and proliferation of Teff cells .…”