Quanlin Liu
Jiahua Liu
Shige Wang
Nabuqi Bao
Xinya Zhao1
Lei Wang- 1First Affiliated Hospital of Dalian Medical University, Dalian, China
- 2Jinqiu Hospital, Shenyang, China
Nucleotide metabolism plays a pivotal role in the onset and progression of various human diseases, including pancreatic disorders. As fundamental biomolecules, nucleotides are essential for DNA and RNA synthesis, energy production, and cell signaling. Disruptions in nucleotide metabolic pathways have been linked to altered cell proliferation, apoptosis, and immune responses—critical processes in the development of pancreatic diseases. In pancreatic cancer, metabolic changes in nucleotides facilitate rapid tumor cell proliferation and enhance chemotherapy resistance. Recent studies have concentrated on identifying specific enzymes and pathways within nucleotide metabolism as potential therapeutic targets. Targeted interventions, such as modulating RRM2, TS, and other key enzymes or disrupting the PI3K/AKT/mTOR pathway, have demonstrated potential in reducing tumor growth and inflammation in pancreatic tissue. This review provides an overview of the latest advancements in the understanding of nucleotide metabolism in pancreatic cancer pathogenesis, emphasizing diagnostic and therapeutic strategies that may improve patient outcomes.
1 Introduction
Abnormalities in nucleotide metabolism have been shown to play a critical role in the onset, progression, and treatment response of acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic cancer (PC). PC, an aggressively invasive malignancy with an exceptionally high mortality rate, is often referred to as the “King of Cancers.” As one of the deadliest cancers globally, its subtle early symptoms frequently result in diagnosis at advanced stages. Treatment options for PC remain limited, and the prognosis is poor, highlighting the importance of a deeper understanding of its molecular mechanisms to develop more effective therapies (1).
In pancreatic diseases, disruptions in cellular metabolism are fundamental. Nucleotide metabolism, a key aspect of cellular metabolism, serves not only as a critical precursor for DNA and RNA synthesis but also plays an essential role in biological processes such as cell proliferation, survival, aging, and apoptosis. In PC cells, nucleotide metabolic pathways are frequently reprogrammed to support rapid tumor cell proliferation and resistance to chemotherapy (2). Research has clarified that nucleotide metabolism operates primarily through two biosynthetic pathways: the de novo synthesis pathway and the salvage pathway (3). PC cells rely heavily on the de novo synthesis pathway to meet the demands of their accelerated growth.
Moreover, nucleotide metabolism is regulated by several signaling pathways, including PI3K/Akt, mTOR, and p53, which significantly influence the initiation and progression of PC. Recent studies have demonstrated that targeting nucleotide metabolism can not only impede tumor growth but also enhance chemotherapy sensitivity (4, 5). Ongoing research is actively identifying new nucleotide-related tumor markers in cancer (6, 7), with increasing attention being paid to personalized treatment approaches for patients (8).
Thus, a comprehensive investigation into the role of nucleotide metabolism in PC offers insights into potential mechanisms for its treatment and prevention, while also paving the way for novel targeted therapeutic strategies in clinical practice. This review examines the core pathways of nucleotide metabolism, explores its relationship with PC, and highlights the significant alterations in nucleotide metabolism observed in PC.
2 Nucleotide metabolism
Nucleotide metabolism is a crucial metabolic pathway in the human body. Recent advancements, driven by global scientific collaboration, have progressively clarified the structure and function of key enzymes involved, shedding light on this complex and essential process. Nucleotide metabolism encompasses the de novo synthesis pathways of pyrimidines and purines, the salvage synthesis pathway (SSP), and nucleotide catabolism (Figures 1, 2).
Figure 1. Core pathways of purine nucleotide metabolism: de novo synthesis, salvage synthesis, and catabolism. This diagram comprehensively illustrates the core biosynthetic and catabolic networks of purine nucleotides (e.g., AMP, GMP), covering the de novo synthesis, salvage synthesis, and catabolism of purines, along with some regulatory mechanisms. Solid arrows indicate the main metabolic pathways, while the dashed line indicates the process from PRA to IMP. The double-underlined arrows and diamond boxes highlight feedback inhibition, and the dark color emphasizes key components. This schematic diagram describes the various steps of purine metabolism as comprehensively as possible, and serves as a comprehensive reference for understanding purine nucleotide metabolism in normal pancreatic diseases. RDS, rate-determining step; R5P, Ribose-5-phosphate; PRA, Phosphoribosylamine.
Figure 2. Core pathways of pyrimidine nucleotide metabolism: de novo synthesis, salvage synthesis, and catabolism. This diagram comprehensively illustrates the core biosynthetic and catabolic networks of pyrimidine nucleotides (e.g., UMP, CTP, dTTP), covering the de novo synthesis, salvage synthesis, and catabolism of pyrimidines, along with some regulatory mechanisms. The solid arrows represent the major metabolic flow. The double-underlined arrows and diamond boxes highlight feedback inhibition, and the dark color emphasizes key components. This schematic diagram describes the various steps of pyrimidine metabolism as comprehensively as possible, and serves as a comprehensive reference for understanding pyrimidine nucleotide metabolism in normal pancreatic diseases. OPRT, Orotate phosphoribosyltransferase; OMPDC, Orotidine-5’-monophosphate decarboxylase.
Typically, the de novo synthesis pathway is the primary route of nucleotide metabolism, while the SSP is utilized only in specific regions where relevant enzymes are insufficient. The de novo purine synthesis pathway begins with ribose-5-phosphate (R5P), which is enzymatically converted into 5-phosphoribose-1-pyrophosphate (PRPP) (9). PRPP is subsequently transformed into 5-phosphoribosamine (PAR), and through nine catalytic steps facilitated by five enzymes, PAR yields inosine monophosphate (IMP) (10). IMP is then converted to adenosine monophosphate (AMP) and guanosine monophosphate (GMP) by various enzymes (11). In purine salvage synthesis, hypoxanthine and guanine bind with PRPP to form IMP and GMP, respectively, while adenine is converted to AMP. The purine catabolic pathway involves the breakdown of AMP into hypoxanthine, which, along with guanine from GMP, is oxidized to xanthine and ultimately to uric acid by xanthine oxidase (XO). Excess AMP and GMP exert negative feedback inhibition on the production of adenylosuccinate synthetase (ADSS) and adenine, while excess GMP inhibits inosine monophosphate dehydrogenase (IMPDH) and guanine production.
The de novo pyrimidine synthesis pathway begins with the multifunctional CAD protein complex, which includes carbamoyl-phosphate synthetase II (CPSII), aspartate carbamoyltransferase (ATC), and dihydroorotase (DHOase) (12). This complex catalyzes the synthesis of carbamoyl phosphate, which, along with glutamine and aspartic acid, is ultimately converted into orotic acid through four key steps (13). As pyrimidine synthesis requires oxygen, it is closely linked to mitochondrial function and cellular oxygen availability. Orotic acid then undergoes reactions in the cytoplasm to form uridine monophosphate (UMP), which is subsequently converted into UDP and then into dCTP and dTTP. Under resting conditions or when pyrimidine demand is low, the body prefers the SSP. Uridine and cytidine are directly phosphorylated to UMP or CMP by intracellular enzymes, replenishing the pyrimidine pool through further reactions. Pyrimidine catabolism involves the degradation of cytosine and uracil into β-alanine, NH3, and CO2, while thymine is broken down into β-aminoisobutyric acid, NH3, and CO2.
3 Nucleotide metabolism and disease pathogenesis
3.1 Precancerous lesions
The pathogenesis of PC is a prolonged, multifactorial process, involving a series of genetic and cellular changes. It is characterized by various pathological alterations and progresses through several precursor lesions, including pancreatic acinar cell transformation (ADM), pancreatic intraepithelial neoplasia (PanIN), and intraductal pancreatic mucinous neoplasms (IPMN).
ADM refers to the reversible transdifferentiation of pancreatic acinar cells into duct-like cells. However, under the influence of carcinogenic drivers and chronic inflammation, ADM can progress to more advanced lesions, such as PanIN (14). PanIN lesions are typically small (< 5mm) and appear as flat or papillary structures within intralobular pancreatic ducts (15). They are classified based on nuclear atypia into three grades: PanIN-1 (low-grade), PanIN-2 (moderate-grade), and PanIN-3 (high-grade). IPMN, on the other hand, is marked by cystic lesions originating from the pancreatic ductal system, which produce mucin. These lesions are categorized into three subtypes: main duct IPMN (MD-IPMN), branch duct IPMN (BD-IPMN), and mixed-type IPMN (MT-IPMN) (16).
Notably, metabolic reprogramming occurs in these precursor lesions, indicating that early pancreatic carcinogenesis involves metabolic adaptations to meet the demands of nucleotide metabolism. Furthermore, metabolic alterations observed at the PanIN/IPMN stage appear to persist into the pancreatic ductal adenocarcinoma (PDAC) stage. In a metabolomic analysis of a PanIN mouse model, intermediates of the purine synthesis pathway did not increase as carcinogenesis progressed. In fact, levels of dAMP, GMP, and dGMP decreased. However, there was a noticeable increase in ADP and ATP levels, suggesting heightened cellular energy metabolism. This change may indicate either an enhancement or a subtle modification of the purine synthesis pathway, which warrants further investigation. In contrast, the pyrimidine synthesis pathway showed more pronounced upregulation during carcinogenesis. Levels of UDP and CMP increased, while the concentration of carbamoylaspartate, an early product of pyrimidine synthesis, decreased (17). In summary, current research indicates that alterations in these metabolites and their regulatory genes can indeed be observed in precancerous lesion models. However, whether these alterations act as functional drivers of disease occurrence remains unclear, and this gap highlights the need for further mechanistic studies.
3.2 Pancreatic carcinogenesis mechanisms
PC is a highly lethal malignancy that can be classified into two major categories based on its cellular origin: pancreatic epithelial-derived and non-pancreatic epithelial-derived cancers. The majority of PC cases are pancreatic epithelial-derived, primarily comprising PDAC, which accounts for over 90% of cases. This category also includes adenosquamous carcinoma, colloid carcinoma, and undifferentiated carcinoma (18). Tumorigenesis in PDAC is driven by genomic instability, including somatic mutations, chromosomal rearrangements, copy number alterations, and epigenetic modifications. Two principal molecular models of PDAC pathogenesis provide differing views on tumor progression: one proposes a gradual, stepwise progression, while the other suggests a punctuated evolutionary pattern (19). Apart from genetic alterations, nucleotide metabolism-related mechanisms also play crucial roles in PDAC progression. Through a complex regulatory network, nucleotide metabolism-related mechanisms directly or indirectly affect PDAC progression. Figure 3 shows the mechanism related to nucleotide metabolism in pancreatic cancer cells.
Figure 3. Schematic of nucleotide metabolism-related mechanisms in pancreatic cancer cells (by Figdraw). This diagram illustrates the mechanisms involved in nucleotide metabolism within pancreatic cancer cells, covering DNA synthesis, pyrimidine precursor production, nucleotide synthesis gene regulation, and acetate metabolism. Factors such as RRM2, PGK1, and DHODH, which are highly related to nucleotide metabolism in pancreatic cancer, play crucial functional and regulatory roles. This framework outlines the changes in nucleotide metabolic pathways in certain pancreatic cancer cells and highlights potential drug targets and regulatory mechanisms. RDS, rate-determining step; 1,3-BPG, 1,3-Bisphosphoglycerate; 3-PG, 3-Phosphoglycerate; Pyr Syn, Pyrimidine Synthesis; Pyr Prec, Pyrimidine Precursor; DHO, Dihydroorotate; SAT1 Act, SAT1 Activation.
As in other solid tumors, angiogenesis plays a pivotal role in PC. It is considered a key rate-limiting step in both tumor growth and metastasis. In PC, angiogenesis is often induced by the hypoxic environment within the tumor. Tumor cells respond by producing and releasing a variety of growth factors, including vascular endothelial growth factor receptor (VEGFR) and neuropilin (NRP), which mediate and promote angiogenesis (20). Additionally, PC cells exhibit a unique pathological structure known as basal microvillus supply, which supports high metabolic activity. These structures are responsible for glucose transport into tumor cells and display endocytic properties similar to those of normal microvessels, facilitating nutrient exchange in the tumor microvasculature. This interaction may also enhance the activity of phagocytes and macrophages in PDAC (21).
The tumor microenvironment (TME) of PDAC consists primarily of various non-tumor cells, including cancer-associated fibroblasts (CAFs), endothelial cells (ECs), nerve cells, and immune cells, mainly myeloid cells. The TME is also rich in extracellular matrix (ECM) components such as growth factors, cytokines, hyaluronic acid (HA), and collagen. Notably, the TME of PDAC is strongly immunosuppressed, with a marked absence of highly active infiltrating CD8+ T cells (22). This unique immunosuppressive environment plays a critical role in promoting the proliferation, migration, and drug resistance of PDAC. PC cells meet the demands of rapid proliferation by upregulating purine and pyrimidine synthesis pathways. Additionally, the released metabolites can modulate the activity of immune cells (23, 24). Within the TME, tumor-associated macrophages (TAMs) undergo metabolic reprogramming from an M1 phenotype, which is pro-inflammatory, to an M2 phenotype, which is immunosuppressive. This shift inhibits the function of effector T cells, promoting tumor immune escape and progression. High concentrations of metabolites such as adenosine suppress T cell proliferation and cytotoxic function by binding to adenosine receptors on the surface of T cells (25, 26). Moreover, regulatory T cells (Tregs) accumulate in the PC microenvironment, further depleting critical metabolites like ATP and impairing the antitumor responses of effector T cells, thereby contributing to tumor immune evasion (27–29). Metabolic reprogramming within the TME alters the utilization of metabolites by immune cells, weakening their antitumor function and ultimately facilitating tumor growth and metastasis.
In addition to immune cells, current studies also implicate purinergic signaling in CAF and PDAC crosstalk. In PDAC the CD39/CD73 pathway (ATP-AMP-adenosine axis) is markedly upregulated, yielding high extracellular adenosine that suppresses CD8+ T and NK cells while promoting Tregs and MDSCs (30). Importantly, CAFs and tumor cells are major sources of this pathway (30, 31). CAFs express CD73 (NT5E) and other ectonucleotidases to produce adenosine, reinforcing local immune evasion (30, 31). For example, multiscale profiling in PDAC found that CD73+ CAFs cluster near tumor cells and likely mediate metabolic crosstalk and immunosuppression in the dense stroma (31). Single-cell analysis and spatial data show that PDAC cells and CAFs are accompanied by higher scores of purine metabolism (32). Co-culture experiments further show that silencing NT5E (CD73) in PDAC cells reduced their invasion/proliferation, but this effect was largely rescued by co-culture with CAFs (32). These findings collectively indicate that CAF‐derived purine metabolites and enzymes drive PDAC progression and immune suppression via metabolic reprogramming of the tumor microenvironment (e.g. ATP/AMP conversion to adenosine). Targeting this CAF-purine axis may represent a strategy to disrupt tumor‐promoting metabolic symbiosis and restore anti‐tumor immunity in PDAC.
3.3 Changes in nucleotide metabolism-related genes and enzymes in pancreatic diseases
The role of nucleotide metabolism in pancreatic diseases has garnered increasing attention, with numerous related genes and their functions now being identified. Table 1 summarizes several relevant genes, while Table 2 (33–81) provides a brief overview of the mechanisms associated with these genes. Below are some key changes in genes and enzymes.
Table 1. Forty-two genes associated with nucleotide metabolism.
Table 2. Genetic mechanisms of the 42 genes: brief elaboration.
3.3.1 Purine metabolism related
The elevated expression of adenosine succinate lyase (ADSL) in cancer is linked to tumor invasion and poor prognosis. This effect is mediated through the inhibition of Carma3 expression, which influences resistance to gemcitabine (also known as 2,2-difluorodeoxycytidine, dFdC), while Nrf2 signaling can regulate ADSL expression. Knockdown of ADSL significantly reduces the responsiveness of PC cells to gemcitabine treatment (82).
Adenosine deaminase (ADA) plays a role in adenosine metabolism by converting adenosine to hypoxanthine. Although its precise role in PC remains unclear, it is known that the serum levels of ADA in patients with pancreatic diseases differ significantly from those in healthy individuals (83), particularly in patients with PC, making it a potential area for further investigation. CD73 (NT5E), a key enzyme that converts AMP to adenosine, has been explored in PC, with the CD73 inhibitor AB680 showing promise (84). Several CD73 inhibitors are currently in clinical trials (85). Research on the Nudix hydrolase superfamily in PC is still limited. These enzymes hydrolyze toxic nucleoside triphosphates, and NUDT15 has emerged as a potential biomarker (86), with its high expression strongly correlating with early postoperative recurrence risk. Further investigation into its underlying mechanisms is needed.
Adenylate kinase (AK) regulates multiple cellular functions, including maintaining adenine nucleotide metabolic homeostasis, activating the AK-AMP-AMPK signaling pathway, regulating the cell cycle, proliferation, and intracellular energy transfer, as well as mitochondrial ATP distribution. Studies suggest that AK expression is upregulated in metastatic pancreatic endocrine tumors, with overexpression potentially promoting tumorigenesis. AK also influences the efficacy of adjuvant therapy by inducing epithelial-mesenchymal transition (EMT). Compared to normal tissues, AK2 expression is elevated in PDAC, though its exact role requires further exploration (87). In studies of adenylate kinase 4 pseudogene 1 (AK4P1), both AK4 and AK4P1 were identified as oncogenic and significantly upregulated in PDAC (88).
Phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which catalyzes the conversion of SAICAR to AICAR in purine biosynthesis, is overexpressed in PDAC. Research indicates that its knockdown suppresses cell proliferation, colony formation, invasion, motility, and spheroid formation, suggesting that PAICS targeting may offer a promising therapeutic strategy for PDAC (69).
The NT5DC family includes evolutionarily conserved 5’-nucleotidases that catalyze intracellular nucleotide hydrolysis. Recent studies suggest that NT5DC2 may serve as both a therapeutic target and a valuable biomarker for personalized treatment in patients with PC (89).
3.3.2 Pyrimidine metabolism related
Upregulation of dihydropyrimidine dehydrogenase (DPYD), which catalyzes the catabolism and inactivation of 5-fluorouracil (5-FU) in pyrimidine-based chemotherapy, has been linked to increased proliferation, invasion, angiogenesis, and resistance to 5-FU treatment in PC. Elevated DPYD expression in PDAC not only enhances pyrimidine degradation but also promotes cell proliferation and invasiveness, accompanied by upregulation of MMP9 and MEP1A (90). This suggests potential therapeutic benefits of targeting DPYD in clinical settings.
Dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine nucleotide synthesis, has demonstrated promising preclinical activity. However, DHODH inhibitors have largely failed to show efficacy in PDAC and other solid tumors in multiple clinical trials, with cancer cells seemingly evading inhibition of this metabolic enzyme. The underlying mechanisms remain unclear, and further investigations are ongoing (91, 92). Teriflunomide, the active metabolite of the immunosuppressant leflunomide, directly inhibits DHODH and has been used in the treatment of rheumatoid arthritis (93). Its potential role in PC remains to be explored.
Research on the TYMS gene in PC is gradually progressing. Literature suggests that TYMS is upregulated in PC, with varying expression levels across different histological grades and clinical stages. High TYMS expression is associated with poor prognosis in patients (94). Additionally, the TYMS gene encodes thymidylate synthase (TS).
TS plays a pivotal role in the synthesis of deoxythymidine monophosphate (dTMP) by catalyzing the conversion of deoxyuridine monophosphate (dUMP) to dTMP. As one of the earliest identified anti-cancer targets (95), its role in PC remains incompletely understood. Some studies report that TS activity in PC is significantly higher than in normal pancreatic tissue, though lower than in other solid tumors (96). Additionally, high TS expression correlates with advanced clinical stages and poor prognosis, making TS a potential biomarker for the diagnosis and prognosis of patients with PC (94).
5-FU, widely used in the treatment of various gastrointestinal cancers, including PC, targets TS. Although 5-FU’s efficacy in PC tissue may be lower than in normal tissue (96), it remains a cornerstone of treatment. As a TS inhibitor, 5-FU interferes with dTMP production, thereby inhibiting DNA synthesis in cancer cells (97, 98). Standard regimens like FOLFIRINOX (oxaliplatin, irinotecan, 5-FU, and leucovorin) leverage the effects of 5-FU and are commonly used for the initial treatment of metastatic pancreatic adenocarcinoma (MPC) (99, 100). Overexpression of TS has been closely linked to 5-FU resistance. 5-FU binds to TS through its active metabolite, fluorodeoxyuridine monophosphate (FdUMP), inhibiting TS activity and disrupting DNA synthesis. However, TS overexpression diminishes the therapeutic effects of 5-FU. Therefore, inhibiting TS activity can enhance 5-FU efficacy (101, 102). Moreover, combining strategies to synergistically inhibit TS activity may further improve therapeutic outcomes. Tumor genotypes and metabolic adaptations in the TME also modulate TS activity, highlighting the need for personalized TS-targeted therapies based on patient stratification (103, 104).
Deoxycytidine kinase (DCK) is a key enzyme involved in the SSP of deoxyribonucleotides and is crucial for the phosphorylation of cytidine, thus playing an essential role in maintaining normal DNA metabolism. Given that DCK affects the metabolism of gemcitabine, a first-line nucleoside analog drug used to treat PC, much of the existing literature focuses on its role in gemcitabine metabolism, though its direct impact on PC remains underexplored. Some studies indicate that in idiopathic pulmonary fibrosis (IPF), DCK is a downstream target of hypoxia and contributes to alveolar epithelial cell proliferation, while in chronic obstructive pulmonary disease (COPD), elevated DCK levels can trigger apoptosis in chronic lung disease cells (105). However, it is clear that during PC treatment with gemcitabine, DCK expression decreases as the disease progresses (106). Research into DCK’s regulatory mechanisms in PC is still incomplete and warrants further investigation. Clinically, gemcitabine is widely used as a standard treatment for advanced PC. Decreased expression or mutations in DCK are closely associated with gemcitabine resistance, particularly in PC. As a key enzyme in gemcitabine activation, reduced DCK activity results in lower cellular uptake and activation of the drug, thereby compromising its efficacy (107). Increasing DCK expression or activity can enhance the cytotoxic effects of gemcitabine. Specifically, certain metabolic inhibitors may reactivate DCK by modifying the tumor’s metabolic environment, thus restoring gemcitabine efficacy (108). Furthermore, some studies have explored gene therapy approaches to directly introduce the DCK gene into PC tumors. This strategy, when combined with chemotherapy, not only increases DCK activity but also amplifies the drug’s cytotoxicity against cancer cells.
Ribonucleotide reductase M2 (RRM2), a subunit of ribonucleotide reductase (RNR), is responsible for converting ribonucleotides to deoxyribonucleotides, a key step in DNA synthesis. Literature suggests that high RRM2 expression in PC is associated with poor survival rates. Silencing RRM2 inhibits PC cell proliferation and tumor growth by inactivating the PI3K/AKT/mTOR pathway, leading to cell cycle arrest and/or apoptosis (109). As an RNR-inhibiting antimetabolite, gemcitabine remains one of the few FDA-approved drugs for PC treatment (110). Currently, more selective RRM2 inhibitors are under development.
3.3.3 Oncogenic driver genes and other critical genes
The Kirsten Rat Sarcoma (KRAS) gene mutation is the most prevalent mutation across all cancers, including PC. Over 90% of PDAC cases harbor activated KRAS mutations, which are strongly associated with disease progression (111). The KRAS gene encodes a small GTPase protein that functions as a molecular switch for numerous key intracellular signaling pathways. KRAS activity is determined by its binding to either GTP, which activates it, or GDP, which inactivates it. The most common KRAS mutations occur at codon 12 of the oncogene, and include G12D, G12V, and G12R. Oncogenic KRAS activates several critical downstream effector pathways, including the RAF-MEK-ERK MAPK pathway, the PI3K-AKT-mTOR pathway, and the Ral guanine nucleotide exchange factor (RalGEF) pathway. Direct pharmacological targeting of KRAS has historically been considered challenging, but recent studies have identified viable therapeutic strategies for KRAS-targeted therapy (112, 113). Moreover, nucleotide metabolism is a key mediator of KRAS resistance, with oncogenic KRAS contributing to PC progression by regulating nucleotide metabolism (114).
The oncogenic KRAS gene plays a pivotal role in pancreatic disease progression through its interactions with nucleotide metabolism. While past research has primarily targeted its downstream signaling pathways, significant clinical advancements remain elusive (115–117). The link between KRAS and nucleotide metabolism still requires further exploration. Sotorasib and Adagrasib, two KRAS G12C inhibitors, have shown efficacy in various cancers, including non-small cell lung cancer (NSCLC) (118, 119). However, their clinical efficacy in KRAS-mutant PCs is limited by drug resistance and transient therapeutic effects. Although these inhibitors demonstrate potent tumor-suppressive activity during initial treatment (112), acquired resistance inevitably develops with prolonged therapy. These resistance mechanisms extend beyond KRAS itself to include the activation of downstream signaling pathways such as the MAPK and PI3K-AKT-mTOR pathways (120–122). KRAS-mutant tumor cells often rely on enhanced nucleotide metabolic pathways to support rapid cell proliferation. KRAS G12C inhibitors can inhibit tumor growth by altering the metabolic state of tumor cells, particularly affecting the nucleotide synthesis pathway (123). Although KRAS G12C inhibitors show some efficacy when used alone (124), literature suggests that combination therapies may offer a promising direction for overcoming resistance and improving tumor suppression. Clinical exploration of such combination therapies is ongoing (121, 125).
The phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) catalyzes the removal of phosphohistidine and phospholysine modifications from target proteins. LHPP is significantly downregulated in PC tissues and cell lines, and its expression suppresses PC cell proliferation, migration, and invasion while promoting apoptosis through AKT signaling (126, 127). LHPP holds promise not only as a therapeutic target but also as a prognostic biomarker and metabolic regulator, offering novel insights for PC management.
3.4 Advances in targeting nucleotide metabolism for PC therapy and related clinical trials
KRAS has emerged as a central focus of research in PDAC (128). Recent advances have been made in developing direct inhibitors targeting the KRAS-G12C mutation, which have shown promise in treating certain solid tumors. The Phase I/II CodeBreaK 100 trial demonstrated positive effects in PDAC treatment (129), though the efficacy of KRAS inhibitor monotherapy remains limited. Ongoing investigations are exploring adagrasib for KRAS-G12C-mutated PC, with clinical studies examining combination strategies involving KRAS inhibitors and chemotherapy. Furthermore, combining KRAS inhibitors with immunotherapy holds significant potential. Preclinical studies suggest that KRAS-G12C inhibitors may enhance tumor immunogenicity, potentially synergizing with immunotherapies. Building on these findings, the CodeBreaK 101 trial is evaluating sotorasib in combination with pembrolizumab or atezolizumab.
Small molecule inhibitors targeting PAICS are currently under development. Computer-screened PAICS inhibitory compounds have demonstrated some inhibitory effects on PDAC cells (130). Although no clinical trial results are available yet, further in-depth studies are warranted. TS has long been a target of chemotherapy. 5-FU, its derivatives, and gemcitabine are commonly used chemotherapeutic agents in various combination regimens. Efforts are underway in the pharmaceutical field to develop drugs that bypass DCK to overcome DCK-induced gemcitabine resistance (131). Research on ADSL, LHPP, DPYD, RRM2, ADA, and the NT5DC family is ongoing, though clinical trials remain limited. Future advancements are eagerly anticipated.
Moreover, multiple combination therapeutic strategies are being explored, including KRAS inhibitors combined with metabolic pathway inhibition, direct metabolic inhibition paired with immunotherapy, multi-metabolic pathway suppression integrated with targeted therapy, and metabolic reprogramming interventions alongside immunotherapy. However, current research faces several challenges, including suboptimal efficacy, significant population heterogeneity, incompletely controlled overlapping drug toxicities, and excessive physiological burdens on patients. The underlying resistance mechanisms—whether known or yet to be fully characterized—require further investigation.
4 Conclusion and outlook
As insights into the role of nucleotide metabolism in PC continue to deepen, clinical diagnostic and drug development targets are gradually becoming clearer. In terms of early screening and diagnosis, KRAS is the only gene currently with clinically translatable potential for early detection. While PAICS and RRM2 show upregulation at the histological level, their use as early diagnostic biomarkers remains distant. NUDT15, DPYD, TYMS, and DCK hold promise as prognostic markers, while ADSL, ADA, AK, NT5DC, and LHPP exhibit limited potential based on current evidence.
Although the impact of nucleotide metabolic pathways on tumorigenesis and progression is increasingly recognized, and their medical significance shows promise, numerous critical questions remain unresolved. These include the relationship between nucleotide metabolism and early diagnostic biomarkers, the synergistic effects of immunotherapy combined with nucleotide metabolism inhibitors, the cross-tissue and microenvironmental effects of nucleotide metabolism, and the development and clinical application of small molecule inhibitors.
In conclusion, the study of nucleotide metabolism in pancreatic diseases has significant scientific implications and potential clinical applications. Future research is expected to bring breakthroughs in this field, offering new strategies and directions for the treatment of pancreatic diseases.
Author contributions
QL: Methodology, Conceptualization, Investigation, Software, Supervision, Writing – original draft, Data curation. JL: Writing – original draft, Investigation, Software, Conceptualization, Data curation, Supervision, Methodology. SW: Writing – original draft, Data curation, Supervision, Conceptualization, Investigation, Methodology, Software. NB: Visualization, Conceptualization, Validation, Investigation, Writing – original draft, Software, Supervision. XZ: Investigation, Supervision, Writing – original draft, Software, Conceptualization, Visualization, Validation. LW: Conceptualization, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, and/or publication of this article.
Acknowledgments
We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript. Figure 3 was created by Figdraw (www.figdraw.com). The authors would like to express their gratitude to Figdraw.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Qin C, Yang G, Yang J, Ren B, Wang H, Chen G, et al. Metabolism of pancreatic cancer: paving the way to better anticancer strategies. Mol Cancer. (2020) 19:50. doi: 10.1186/s12943-020-01169-7
2. Carneiro TJ, Pinto J, Serrao EM, Barros AS, Brindle KM, and Gil AM. Metabolic profiling of induced acute pancreatitis and pancreatic cancer progression in a mutant Kras mouse model. Front Mol Biosci. (2022) 9. doi: 10.3389/fmolb.2022.937865
3. Chandel NS. Nucleotide metabolism. Cold Spring Harb Perspect Biol. (2021) 13:a040592. doi: 10.1101/cshperspect.a040592
4. Ni C, Liu W, Zheng K, Guo S, Song B, Jing W, et al. PI3K/c-Myc/AFF4 axis promotes pancreatic tumorigenesis through fueling nucleotide metabolism. Int J Biol Sci. (2023) 19:1968–82. doi: 10.7150/ijbs.77150
5. Ali ES and Ben-Sahra I. Regulation of nucleotide metabolism in cancers and immune disorders. Trends Cell Biol. (2023) 33:950–66. doi: 10.1016/j.tcb.2023.03.003
6. Xu S, Zheng Y, Ye M, Shen T, Zhang D, Li Z, et al. Comprehensive pan-cancer analysis reveals EPHB2 is a novel predictive biomarker for prognosis and immunotherapy response. BMC Cancer. (2024) 24:1064. doi: 10.1186/s12885-024-12843-0
7. Xu S, Chen X, Fang J, Chu H, Fang S, Zeng L, et al. Comprehensive analysis of 33 human cancers reveals clinical implications and immunotherapeutic value of the solute carrier family 35 member A2. Front Immunol. (2023) 14:1155182. doi: 10.3389/fimmu.2023.1155182
8. Xu S, Chen X, Ying H, Chen J, Ye M, Lin Z, et al. Multi−omics identification of a signature based on Malignant cell-associated ligand-receptor genes for lung adenocarcinoma. BMC Cancer. (2024) 24:1138. doi: 10.1186/s12885-024-12911-5
9. Hove-Jensen B, Andersen KR, Kilstrup M, Martinussen J, Switzer RL, and Willemoës M. Phosphoribosyl diphosphate (PRPP): biosynthesis, enzymology, utilization, and metabolic significance. Microbiol Mol Biol Rev. (2017) 81:e00040-16. doi: 10.1128/MMBR.00040-16
10. Pedley AM and Benkovic SJ. A new view into the regulation of purine metabolism: the purinosome. Trends Biochem Sci. (2017) 42:141–54. doi: 10.1016/j.tibs.2016.09.009
11. Buey RM, Fernández-Justel D, Jiménez A, and Revuelta JL. The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases. Protein Sci. (2022) 31:e4399. doi: 10.1002/pro.4399
12. del Caño-Ochoa F, Moreno-Morcillo M, and Ramón-Maiques S. Macromolecular Protein Complexes II: Structure and Function. Harris JR and Marles-Wright J, editors. Cham: Springer International Publishing (2019) p. 505–38.
13. Löffler M, Fairbanks LD, Zameitat E, Marinaki AM, and Simmonds HA. Pyrimidine pathways in health and disease. Trends Mol Med. (2005) 11:430–7. doi: 10.1016/j.molmed.2005.07.003
14. Marstrand-Daucé L, Lorenzo D, Chassac A, Nicole P, Couvelard A, and Haumaitre C. Acinar-to-ductal metaplasia (ADM): on the road to pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer. Int J Mol Sci. (2023) 24:9946. doi: 10.3390/ijms24129946
15. Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. (2004) 28:977–87. doi: 10.1097/01.pas.0000126675.59108.80
16. Tanaka M, Fernández-del Castillo C, Kamisawa T, Jang JY, Levy P, Ohtsuka T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. (2017) 17:738–53. doi: 10.1016/j.pan.2017.07.007
17. Vernucci E, Abrego J, Gunda V, Shukla SK, Dasgupta A, Rai V, et al. Metabolic alterations in pancreatic cancer progression. Cancers. (2020) 12:2. doi: 10.3390/cancers12010002
18. Orth M, Metzger P, Gerum S, Mayerle J, Schneider G, Belka C, et al. Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat Oncol. (2019) 14:141. doi: 10.1186/s13014-019-1345-6
19. Ruff SM and Pawlik TM. Molecular classification and pathogenesis of pancreatic adenocarcinoma and targeted therapies: A review. FBL. (2024) 29:101. doi: 10.31083/j.fbl2903101
20. Li S, Xu H-X, Wu C-T, Wang W-Q, Jin W, Gao H-L, et al. Angiogenesis in pancreatic cancer: current research status and clinical implications. Angiogenesis. (2019) 22:15–36. doi: 10.1007/s10456-018-9645-2
21. Saiyin H, Ardito-Abraham CM, Wu Y, Wei Y, Fang Y, Han X, et al. Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma. J Pathol. (2015) 236:142–54. doi: 10.1002/path.4506
22. Falcomatà C, Bärthel S, Schneider G, Rad R, Schmidt-Supprian M, and Saur D. Context-specific determinants of the immunosuppressive tumor microenvironment in pancreatic cancer. Cancer Discov. (2023) 13:278–97. doi: 10.1158/2159-8290.CD-22-0876
23. Xiang H, Yang R, Tu J, Xi Y, Yang S, Lv L, et al. Metabolic reprogramming of immune cells in pancreatic cancer progression. Biomedicine Pharmacotherapy. (2023) 157:113992. doi: 10.1016/j.biopha.2022.113992
24. Hashimoto A and Hashimoto S. Plasticity and tumor microenvironment in pancreatic cancer: genetic, metabolic, and immune perspectives. Cancers. (2024) 16:4094. doi: 10.3390/cancers16234094
25. Habtezion A, Edderkaoui M, and Pandol SJ. Macrophages and pancreatic ductal adenocarcinoma. Cancer Lett. (2016) 381:211–6. doi: 10.1016/j.canlet.2015.11.049
26. Elebo N, Fru P, Omoshoro−Jones J, Patrick Candy G, and Nweke EE. Role of different immune cells and metabolic pathways in modulating the immune response in pancreatic cancer (Review). Mol Med Rep. (2020) 22:4981–91. doi: 10.3892/mmr.2020.11622
27. Hartupee C, Nagalo BM, Chabu CY, Tesfay MZ, Coleman-Barnett J, West JT, et al. Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target. Front Immunol. (2024) 15:1287459. doi: 10.3389/fimmu.2024.1287459
28. Huber M, Brehm CU, Gress TM, Buchholz M, Alashkar Alhamwe B, von Strandmann EP, et al. The immune microenvironment in pancreatic cancer. Int J Mol Sci. (2020) 21:7307. doi: 10.3390/ijms21197307
29. Zhang Y, Lazarus J, Steele NG, Yan W, Lee HJ, Nwosu ZC, et al. Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov. (2020) 10:422–39. doi: 10.1158/2159-8290.CD-19-0958
30. Liu X, Ding Q, Zhang H, Zhang X, Chen Q, and Weng S. The CD39-CD73-adenosine axis: Master regulator of immune evasion and therapeutic target in pancreatic ductal adenocarcinoma. Biochim Biophys Acta Rev Cancer. (2025) 1880:189443. doi: 10.1016/j.bbcan.2025.189443
31. Zhang E, Ding X, Zhang J, Liu W, Liu G, Li M, et al. Multi-omics analysis of polyamine metabolism implicates NT5E/CD73 in the progression of pancreatic cancer. Cancer Lett. (2025) 630:217887. doi: 10.1016/j.canlet.2025.217887
32. Zhang J, Zhang X, Wu R, and Dong CS. Unveiling purine metabolism dysregulation orchestrated immunosuppression in advanced pancreatic cancer and concentrating on the central role of NT5E. Front Immunol. (2025) 16:1569088. doi: 10.3389/fimmu.2025.1569088
33. Dorsey MJ, Rubinstein A, Lehman H, Fausnight T, Wiley JM, and Haddad E. PEGylated recombinant adenosine deaminase maintains detoxification and lymphocyte counts in patients with ADA-SCID. J Clin Immunol. (2023) 43:951–64. doi: 10.1007/s10875-022-01426-y
34. Murugan M, Fedele D, Millner D, Alharfoush E, Vegunta G, and Boison D. Adenosine kinase: An epigenetic modulator in development and disease. Neurochem Int. (2021) 147:105054. doi: 10.1016/j.neuint.2021.105054
35. Boison D and Jarvis MF. Adenosine kinase: A key regulator of purinergic physiology. Biochem Pharmacol. (2021) 187:114321. doi: 10.1016/j.bcp.2020.114321
36. Jarvis MF. Therapeutic potential of adenosine kinase inhibition-Revisited. Pharmacol Res Perspect. (2019) 7:e00506. doi: 10.1002/prp2.506
37. Dutto I, Gerhards J, Herrera A, Souckova O, Škopová V, Smak JA, et al. Pathway-specific effects of ADSL deficiency on neurodevelopment. Elife. (2022) 11:e70518. doi: 10.7554/eLife.70518
38. Taha-Mehlitz S, Bianco G, Coto-Llerena M, Kancherla V, Bantug GR, Gallon J, et al. Adenylosuccinate lyase is oncogenic in colorectal cancer by causing mitochondrial dysfunction and independent activation of NRF2 and mTOR-MYC-axis. Theranostics. (2021) 11:4011–29. doi: 10.7150/thno.50051
39. Dzeja P and Terzic A. Adenylate kinase and AMP signaling networks: metabolic monitoring, signal communication and body energy sensing. Int J Mol Sci. (2009) 10:1729–1772. doi: 10.3390/ijms10041729
40. Cai F, Xu H, Zha D, Wang X, Li P, Yu S, et al. AK2 Promotes the Migration and Invasion of Lung Adenocarcinoma by Activating TGF-β/Smad Pathway In vitro and In vivo. Front Pharmacol. (2021) 12. doi: 10.3389/fphar.2021.714365
41. Fujisawa K, Terai S, Takami T, Yamamoto N, Yamasaki T, Matsumoto T, et al. Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4. J Exp Clin Cancer Res. (2016) 35:48. doi: 10.1186/s13046-016-0322-2
42. Hafen PS, Law AS, Matias C, Miller SG, and Brault JJ. Skeletal muscle contraction kinetics and AMPK responses are modulated by the adenine nucleotide degrading enzyme AMPD1. J Appl Physiol (1985). (2022) 133:1055–66. doi: 10.1152/japplphysiol.00035.2022
43. Ruiz-Ramos A, Velázquez-Campoy A, Grande-García A, Moreno-Morcillo M, and Ramón-Maiques S. Structure and functional characterization of human aspartate transcarbamoylase, the target of the anti-tumoral drug PALA. Structure. (2016) 24:1081–94. doi: 10.1016/j.str.2016.05.001
44. Dash S, Ueda T, Komuro A, Honda M, Sugisawa R, and Okada H. Deoxycytidine kinase inactivation enhances gemcitabine resistance and sensitizes mitochondrial metabolism interference in pancreatic cancer. Cell Death Dis. (2024) 15:131. doi: 10.1038/s41419-024-06531-x
45. Chen BY, Salas JR, Trias AO, Perez Rodriguez A, Tsang JE, Guemes M, et al. Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis. Immunology. (2023) 168:152–69. doi: 10.1111/imm.13569
46. Zhong R, Liang B, Xin R, Zhu X, Liu Z, Chen Q, et al. Deoxycytidine kinase participates in the regulation of radiation-induced autophagy and apoptosis in breast cancer cells. Int J Oncol. (2018) 52:1000–10. doi: 10.3892/ijo.2018.4250
47. Lin GZ, Qiu JW, Deng M, Lin WX, Guo L, and Song YZ. DGUOK-related mitochondrial DNA depletion syndrome: a case report and literature review. Zhongguo Dang Dai Er Ke Za Zhi. (2020) 22:274–9. doi: 10.7499/j.issn.1008-8830.2020.03.017
48. Lešnjaković L, Ganoci L, Bilić I, Šimičević L, Mucalo I, Pleština S, et al. DPYD genotyping and predicting fluoropyrimidine toxicity: where do we stand? Pharmacogenomics. (2023) 24:93–106. doi: 10.2217/pgs-2022-0135
49. van Kuilenburg ABP, Dobritzsch D, Meijer J, Meinsma R, Benoist J-F, Assmann B, et al. Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients. Biochim Biophys Acta (BBA) - Mol Basis Dis. (2010) 1802:639–48. doi: 10.1016/j.bbadis.2010.03.013
50. Zhou T, Qin R, Shi S, Zhang H, Niu C, Ju G, et al. DTYMK promote hepatocellular carcinoma proliferation by regulating cell cycle. Cell Cycle. (2021) 20:1681–91. doi: 10.1080/15384101.2021.1958502
51. Ladner RD, McNulty DE, Carr SA, Roberts GD, and Caradonna SJ. Characterization of distinct nuclear and mitochondrial forms of human deoxyuridine triphosphate nucleotidohydrolase. J Biol Chem. (1996) 271:7745–51. doi: 10.1074/jbc.271.13.7745
52. Zhang D, Yue Y, Jiang S, Li A, Guo A, Wu X, et al. GART expression in rat spinal cord after injury and its role in inflammation. Brain Res. (2014) 1564:41–51. doi: 10.1016/j.brainres.2014.03.044
53. Fernández JR, Byrne B, and Firestein BL. Phylogenetic analysis and molecular evolution of guanine deaminases: from guanine to dendrites. J Mol Evol. (2009) 68:227–35. doi: 10.1007/s00239-009-9205-x
54. Chang Y, Li G, Zhai Y, Huang L, Feng Y, Wang D, et al. Redox regulator GLRX is associated with tumor immunity in glioma. Front Immunol. (2020) 11:580934. doi: 10.3389/fimmu.2020.580934
55. Bianchi-Smiraglia A, Wawrzyniak JA, Bagati A, Marvin EK, Ackroyd J, Moparthy S, et al. Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity. Cell Death Differentiation. (2015) 22:1858–64. doi: 10.1038/cdd.2015.47
56. Baity M, Wang L, Correa AM, Zhang X, Zhang R, Pataer A, et al. Glutathione reductase (GSR) gene deletion and chromosome 8 aneuploidy in primary lung cancers detected by fluorescence in situ hybridization. Am J Cancer Res. (2019) 9:1201–11.
57. Sakumi K, Abolhassani N, Behmanesh M, Iyama T, Tsuchimoto D, and Nakabeppu Y. ITPA protein, an enzyme that eliminates deaminated purine nucleoside triphosphates in cells. Mutat Research/Genetic Toxicol Environ Mutagenesis. (2010) 703:43–50. doi: 10.1016/j.mrgentox.2010.06.009
58. Simone PD, Pavlov YI, and Borgstahl GEO. ITPA (inosine triphosphate pyrophosphatase): from surveillance of nucleotide pools to human disease and pharmacogenetics. Mutat Res. (2013) 753:131–46. doi: 10.1016/j.mrrev.2013.08.001
59. Huang L, Guo Z, Wang F, and Fu L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther. (2021) 6:386. doi: 10.1038/s41392-021-00780-4
60. Hindupur SK, Colombi M, Fuhs SR, Matter MS, Guri Y, Adam K, et al. The protein histidine phosphatase LHPP is a tumour suppressor. Nature. (2018) 555:678–82. doi: 10.1038/nature26140
61. Moniz LS, Surinova S, Ghazaly E, Velasco LG, Haider S, Rodríguez-Prados JC, et al. Phosphoproteomic comparison of Pik3ca and Pten signalling identifies the nucleotidase NT5C as a novel AKT substrate. Sci Rep. (2017) 7:39985. doi: 10.1038/srep39985
62. Barz MJ, Hof J, Groeneveld-Krentz S, Loh JW, Szymansky A, Astrahantseff K, et al. Subclonal NT5C2 mutations are associated with poor outcomes after relapse of pediatric acute lymphoblastic leukemia. Blood. (2020) 135:921–33. doi: 10.1182/blood.2019002499
63. Cros-Perrial E and Jordheim LP. A phenotypic journey into NT5DC proteins in cancer and other diseases. Exp Cell Res. (2025) 446:114468. doi: 10.1016/j.yexcr.2025.114468
64. Scaletti E, Huschmann FU, Mueller U, Weiss MS, and Sträter N. Substrate binding modes of purine and pyrimidine nucleotides to human ecto-5’-nucleotidase (CD73) and inhibition by their bisphosphonic acid derivatives. Purinergic Signal. (2021) 17:693–704. doi: 10.1007/s11302-021-09802-w
65. Abbas HHK, Alhamoudi KMH, Evans MD, Jones GDD, and Foster SS. MTH1 deficiency selectively increases non-cytotoxic oxidative DNA damage in lung cancer cells: more bad news than good? BMC Cancer. (2018) 18:423. doi: 10.1186/s12885-018-4332-7
66. Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. (2016) 48:367–73. doi: 10.1038/ng.3508
67. Trésaugues L, Lundbäck T, Welin M, Flodin S, Nyman T, Silvander C, et al. Structural basis for the specificity of human NUDT16 and its regulation by inosine monophosphate. PloS One. (2015) 10:e0131507. doi: 10.1371/journal.pone.0131507
68. Scaletti ER, Unterlass JE, Almlöf I, Koolmeister T, Vallin KS, Kapsitidou D, et al. Kinetic and structural characterization of NUDT15 and NUDT18 as catalysts of isoprene pyrophosphate hydrolysis. FEBS J. (2024) 291:4301–22. doi: 10.1111/febs.17202
69. Agarwal S, Chakravarthi BVSK, Kim H-G, Gupta N, Hale K, Balasubramanya SAH, et al. PAICS, a de novo purine biosynthetic enzyme, is overexpressed in pancreatic cancer and is involved in its progression. Trans Oncol. (2020) 13:100776. doi: 10.1016/j.tranon.2020.100776
70. Kato T, Ono H, Fujii M, Akahoshi K, Ogura T, Ogawa K, et al. Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells. PloS One. (2021) 16:e0252917. doi: 10.1371/journal.pone.0252917
71. Yang Y, Lin J, Guo S, Xue X, Wang Y, Qiu S, et al. RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer. Cancer Cell Int. (2020) 20:587. doi: 10.1186/s12935-020-01689-8
72. Iqbal W, Demidova EV, Serrao S, ValizadehAslani T, Rosen G, and Arora S. RRM2B is frequently amplified across multiple tumor types: implications for DNA repair, cellular survival, and cancer therapy. Front Genet. (2021) 12. doi: 10.3389/fgene.2021.628758
73. Coggins SA, Mahboubi B, SChinazi RF, and Kim B. SAMHD1 functions and human diseases. Viruses. (2020) 12:382. doi: 10.3390/v12040382
74. Weagel EG, Burrup W, Kovtun R, Velazquez EJ, Felsted AM, Townsend MH, et al. Membrane expression of thymidine kinase 1 and potential clinical relevance in lung, breast, and colorectal Malignancies. Cancer Cell Int. (2018) 18:135. doi: 10.1186/s12935-018-0633-9
75. Berardo A, Domínguez-González C, Engelstad K, and Hirano M. Advances in thymidine kinase 2 deficiency: clinical aspects, translational progress, and emerging therapies. J Neuromuscul Dis. (2022) 9:225–35. doi: 10.3233/JND-210786
76. Liu Y, Lu Y, Xu Z, Ma X, Chen X, and Liu W. Repurposing of the gold drug auranofin and a review of its derivatives as antibacterial therapeutics. Drug Discov Today. (2022) 27:1961–73. doi: 10.1016/j.drudis.2022.02.010
77. Tarar A, Alyami EM, and Peng C-A. Mesenchymal stem cells anchored with thymidine phosphorylase for doxifluridine-mediated cancer therapy. RSC Adv. (2021) 11:1394–403. doi: 10.1039/D0RA10263F
78. Wang L, Shi C, Yu J, and Xu Y. FOXM1-induced TYMS upregulation promotes the progression of hepatocellular carcinoma. Cancer Cell Int. (2022) 22:47. doi: 10.1186/s12935-021-02372-2
79. Lee LD, Pozios I, Liu V, Nachbichler SB, Böhmer D, Kamphues C, et al. Thymidine phosphorylase induction by ionizing radiation antagonizes 5-fluorouracil resistance in human ductal pancreatic adenocarcinoma. Radiat Environ Biophys. (2022) 61:255–62. doi: 10.1007/s00411-022-00962-w
80. Luo L, Zhang J, Tang H, Zhai D, Huang D, Ling L, et al. LncRNA SNORD3A specifically sensitizes breast cancer cells to 5-FU by sponging miR-185-5p to enhance UMPS expression. Cell Death Dis. (2020) 11:329. doi: 10.1038/s41419-020-2557-2
81. Bortolotti M, Polito L, Battelli MG, and Bolognesi A. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol. (2021) 41:101882. doi: 10.1016/j.redox.2021.101882
82. Hsu T-W, Wang W-Y, Chen A, Chiu C-F, Liao P-H, Chen H-A, et al. Nrf2-mediated adenylosuccinate lyase promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma cells through ferroptosis escape. J Cell Physiol. (2024) 239:e31416. doi: 10.1002/jcp.31416
83. Ibiş M, Köklü S, Yilmaz FM, Başar Ö, Yilmaz G, Yüksel O, et al. Serum adenosine deaminase levels in pancreatic diseases. Pancreatology. (2007) 7:526–30. doi: 10.1159/000108970
84. Chang A and Hao J. A tumor intrinsic role of CD73 in pancreatic adenocarcinoma. Ann Pancreatic Cancer. (2022) 5:9. doi: 10.21037/apc-2022-2
85. Bi C, Patel JS, and Liang SH. Development of CD73 inhibitors in tumor immunotherapy and opportunities in imaging and combination therapy. J Medicinal Chem. (2025) 68:6860–9. doi: 10.1021/acs.jmedchem.4c02151
86. Hughes DL, Willenbrock F, Soonawalla Z, Mukherjee S, and O’Neill E. Predicting early disease recurrence of pancreatic cancer following surgery: determining the role of NUDT15 as a prognostic biomarker. Curr Oncol. (2022) 29:2516–29. doi: 10.3390/curroncol29040206
87. Ni D, Wu J, Pan J, Liang Y, Xu Z, Yan Z, et al. The value of a metabolic and immune-related gene signature and adjuvant therapeutic response in pancreatic cancer. Front Genet. (2024) 15:1475378. doi: 10.3389/fgene.2024.1475378
88. Li L, Deng T, Zhang Q, Yang Y, Liu Y, Yuan L, et al. AK4P1 is a cancer-promoting pseudogene in pancreatic adenocarcinoma cells whose transcripts can be transmitted by exosomes. Oncol Lett. (2022) 23:163. doi: 10.3892/ol.2022.13283
89. Yu X, Sun R, Yang X, He X, Guo H, and Ou C. The NT5DC family: expression profile and prognostic value in pancreatic adenocarcinoma. J Cancer. (2023) 14:2274–88. doi: 10.7150/jca.85811
90. Kato H, Sato M, Naiki-Ito A, Inaguma S, Sano M, Komura M, et al. The role of DPYD and the effects of DPYD suppressor luteolin combined with 5-FU in pancreatic cancer. Cancer Med. (2024) 13:e70124. doi: 10.1002/cam4.70124
91. Mullen NJ, Thakur R, Shukla SK, Chaika NV, Kollala SS, Wang D, et al. ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer. Cancer Lett. (2023) 552:215981. doi: 10.1016/j.canlet.2022.215981
92. Zhang H, Santana-Codina N, Yu Q, Poupault C, Campos C, Qin X, et al. De novo pyrimidine biosynthesis inhibition synergizes with BCL-X(L) targeting in pancreatic cancer. Nat Commun. (2025) 16:6987. doi: 10.1038/s41467-025-61242-x
93. Buettner R, Morales C, Wu X, Sanchez JF, Li H, Melstrom LG, et al. Leflunomide Synergizes with Gemcitabine in Growth Inhibition of PC Cells and Impairs c-Myc Signaling through PIM Kinase Targeting. Mol Ther Oncolytics. (2019) 14:149–58. doi: 10.1016/j.omto.2019.04.006
94. Fu Z, Jiao Y, Li Y, Ji B, Jia B, and Liu B. TYMS presents a novel biomarker for diagnosis and prognosis in patients with pancreatic cancer. Med (Baltimore). (2019) 98:e18487. doi: 10.1097/MD.0000000000018487
95. Siddiqui A, Vazakidou ME, Schwab A, Napoli F, Fernandez-Molina C, Rapa I, et al. Thymidylate synthase is functionally associated with ZEB1 and contributes to the epithelial-to-mesenchymal transition of cancer cells. J Pathol. (2017) 242:221–33. doi: 10.1002/path.4897
96. Nakahara O, Takamori H, Tanaka H, Sakamoto Y, Ikuta Y, Furuhashi S, et al. Clinical significance of dihydropyrimidine dehydrogenase and thymidylate synthase expression in patients with pancreatic cancer. Int J Clin Oncol. (2010) 15:39–45. doi: 10.1007/s10147-009-0008-2
97. van der Zee JA, van Eijck CHJ, Hop WCJ, van Dekken H, Dicheva BM, Seynhaeve ALB, et al. Expression and prognostic significance of thymidylate synthase (TS) in pancreatic head and periampullary cancer. Eur J Surg Oncol (EJSO). (2012) 38:1058–64. doi: 10.1016/j.ejso.2012.04.013
98. Zhang Q, Zhao Y-p, Liao Q, Hu Y, Xu Q, Zhou L, et al. Associations between gene polymorphisms of thymidylate synthase with its protein expression and chemosensitivity to 5-fluorouracil in pancreatic carcinoma cells. Chin Med J. (2011) 124:262–7. doi: 10.3760/cma.j.issn.0366-6999.2011.02.021
99. Klein-Brill A, Amar-Farkash S, Lawrence G, Collisson EA, and Aran D. Comparison of FOLFIRINOX vs gemcitabine plus nab-paclitaxel as first-line chemotherapy for metastatic pancreatic ductal adenocarcinoma. JAMA Netw Open. (2022) 5:e2216199. doi: 10.1001/jamanetworkopen.2022.16199
100. Ozaka M, Ishii H, Sato T, Ueno M, Ikeda M, Uesugi K, et al. A phase II study of modified FOLFIRINOX for chemotherapy-naïve patients with metastatic pancreatic cancer. Cancer Chemotherapy Pharmacol. (2018) 81:1017–23. doi: 10.1007/s00280-018-3577-9
101. Suetsugu T, Mori R, Futamura M, Fukada M, Tanaka H, Yasufuku I, et al. Mechanism of acquired 5FU resistance and strategy for overcoming 5FU resistance focusing on 5FU metabolism in colon cancer cell lines. Oncol Rep. (2021) 45:27. doi: 10.3892/or.2021.7978
102. Haritha NH, Nawab A, Vijayakurup V, Anto NP, Liju VB, Alex VV, et al. Targeting thymidylate synthase enhances the chemosensitivity of triple-negative breast cancer towards 5-FU-based combinatorial therapy. Front Oncol. (2021) 11. doi: 10.3389/fonc.2021.656804
103. Matuszyk J. MALAT1-miRNAs network regulate thymidylate synthase and affect 5FU-based chemotherapy. Mol Med. (2022) 28:89. doi: 10.1186/s10020-022-00516-2
104. Sethy C and Kundu CN. 5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition. Biomedicine Pharmacotherapy. (2021) 137:111285. doi: 10.1016/j.biopha.2021.111285
105. Hu Q, Qin Y, Xiang J, Liu W, Xu W, Sun Q, et al. dCK negatively regulates the NRF2/ARE axis and ROS production in pancreatic cancer. Cell Prolif. (2018) 51:e12456. doi: 10.1111/cpr.12456
106. Sebastiani V, Ricci F, Rubio-Viqueira B, Kulesza P, Yeo CJ, Hidalgo M, et al. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res. (2006) 12:2492–7. doi: 10.1158/1078-0432.CCR-05-2655
107. Maity G, Ghosh A, Gupta V, Haque I, Sarkar S, Das A, et al. CYR61/CCN1 regulates dCK and CTGF and causes gemcitabine-resistant phenotype in pancreatic ductal adenocarcinoma. Mol Cancer Ther. (2019) 18:788–800. doi: 10.1158/1535-7163.MCT-18-0899
108. Amrutkar M and Gladhaug IP. Pancreatic cancer chemoresistance to gemcitabine. Cancers. (2017) 9:157. doi: 10.3390/cancers9110157
109. Shan J, Wang Z, Mo Q, Long J, Fan Y, Cheng L, et al. Ribonucleotide reductase M2 subunit silencing suppresses tumorigenesis in pancreatic cancer via inactivation of PI3K/AKT/mTOR pathway. Pancreatology. (2022) 22:401–13. doi: 10.1016/j.pan.2022.03.002
110. Huff SE, Winter JM, and Dealwis CG. Inhibitors of the cancer target ribonucleotide reductase, past and present. Biomolecules. (2022) 12:815. doi: 10.3390/biom12060815
111. Nusrat F, Khanna A, Jain A, Jiang W, Lavu H, Yeo CJ, et al. The clinical implications of KRAS mutations and variant allele frequencies in pancreatic ductal adenocarcinoma. J Clin Med. (2024) 13:2103. doi: 10.3390/jcm13072103
112. Stickler S, Rath B, and Hamilton G. Targeting KRAS in pancreatic cancer. Oncol Res. (2024) 32:799–805. doi: 10.32604/or.2024.045356
113. Bannoura SF, Uddin MH, Nagasaka M, Fazili F, Al-Hallak MN, Philip PA, et al. Targeting KRAS in pancreatic cancer: new drugs on the horizon. Cancer Metastasis Rev. (2021) 40:819–35. doi: 10.1007/s10555-021-09990-2
114. Santana-Codina N, Roeth AA, Zhang Y, Yang A, Mashadova O, Asara JM, et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat Commun. (2018) 9:4945. doi: 10.1038/s41467-018-07472-8
115. Cowzer D, Zameer M, Conroy M, Kolch W, and Duffy AG. Targeting KRAS in pancreatic cancer. J Pers Med. (2022) 12:799–805. doi: 10.3390/jpm12111870
116. Luo J. KRAS mutation in pancreatic cancer. Semin Oncol. (2021) 48:10–8. doi: 10.1053/j.seminoncol.2021.02.003
117. Buscail L, Bournet B, and Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol. (2020) 17:153–68. doi: 10.1038/s41575-019-0245-4
118. Peng T-R, Wu T-W, Yi T-Y, and Wu A-J. Comparative efficacy of adagrasib and sotorasib in KRAS G12C-mutant NSCLC: insights from pivotal trials. Cancers. (2024) 16:3676. doi: 10.3390/cancers16213676
119. Boumelha J, Molina-Arcas M, and Downward J. Facts and hopes on RAS inhibitors and cancer immunotherapy. Clin Cancer Res. (2023) 29:5012–20. doi: 10.1158/1078-0432.CCR-22-3655
120. Dilly J, Hoffman MT, Abbassi L, Li Z, Paradiso F, Parent BD, et al. Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer. Cancer Discov. (2024) 14:2135–61. doi: 10.1158/2159-8290.CD-24-0177
121. Miyazaki S, Kitazawa M, Nakamura S, Koyama M, Yamamoto Y, Hondo N, et al. Targeting KRAS-mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2. Mol Oncol. (2024) 19:377–390. doi: 10.1002/1878-0261.13751
122. Yang X and Wu H. RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms. J Hematol Oncol. (2024) 17:108. doi: 10.1186/s13045-024-01631-9
123. Zhang Y, Li C, Xia C, Wah To KK, Guo Z, Ren C, et al. Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo. Cell Communication Signaling. (2022) 20:142. doi: 10.1186/s12964-022-00955-8
124. Strickler JH, Satake H, George TJ, Yaeger R, Hollebecque A, Garrido-Laguna I, et al. Sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer. N Engl J Med. (2023) 388:33–43. doi: 10.1056/NEJMoa2208470
125. Khan S, Wiegand J, Zhang P, Hu W, Thummuri D, Budamagunta V, et al. BCL-X(L) PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRAS(G12C)-mutated cancers. J Hematol Oncol. (2022) 15:23. doi: 10.1186/s13045-022-01241-3
126. Wu F, Chen Y, and Zhu J. LHPP suppresses proliferation, migration, and invasion and promotes apoptosis in pancreatic cancer. Biosci Rep. (2020) 40:BSR20194142. doi: 10.1042/BSR20194142
127. Zhu H, Song C, Li J, Liu Q, Liu M, and Fu L. LHPP suppresses proliferation, migration, and invasion in hepatocellular carcinoma and pancreatic cancer by inhibiting EGFR signaling pathway. Med Oncol. (2023) 40:257. doi: 10.1007/s12032-023-02127-1
128. Linehan A, O’Reilly M, McDermott R, and O’Kane GM. Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies. Front Med. (2024) 11. doi: 10.3389/fmed.2024.1369136
129. Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. (2021) 384:2371–81. doi: 10.1056/NEJMoa2103695
130. Chamani R and Darvand Araghi MH. Introducing new inhibitors of PAICS, a de novo purine biosynthesis enzyme, through structure-based virtual screening. Iranian J Biotechnol. (2025) 23:83–91. doi: 10.30498/ijb.2025.461234.3935
Keywords: nucleotide metabolism, pancreatic cancer, therapeutic targets, pathogenesis, metabolic reprogramming, KRAS mutation, immune microenvironment
Citation: Liu Q, Liu J, Wang S, Bao N, Zhao X and Wang L (2025) Roles of nucleotide metabolism in pancreatic cancer. Front. Immunol. 16:1637768. doi: 10.3389/fimmu.2025.1637768
Received: 29 May 2025; Accepted: 26 September 2025;
Published: 22 October 2025.
Edited by:
Wei Chong, Shandong Provincial Hospital, ChinaReviewed by:
Xiaolong Tang, Hospital of Chengdu University of Traditional Chinese Medicine, ChinaZhe Ji, Tongji University, China
Copyright © 2025 Liu, Liu, Wang, Bao, Zhao and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lei Wang, d2FuZ2xlaTA1MDIxOUAxNjMuY29t
†These authors have contributed equally to this work