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CDA

Official Full Name
cytidine deaminase
Organism
Homo sapiens
GeneID
978
Background
This gene encodes an enzyme involved in pyrimidine salvaging. The encoded protein forms a homotetramer that catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine, respectively. It is one of several deaminases responsible for maintaining the cellular pyrimidine pool. Mutations in this gene are associated with decreased sensitivity to the cytosine nucleoside analogue cytosine arabinoside used in the treatment of certain childhood leukemias. [provided by RefSeq, Jul 2008]
Synonyms
CDD;
Bio Chemical Class
Carbon-nitrogen hydrolase
Protein Sequence
MAQKRPACTLKPECVQQLLVCSQEAKKSAYCPYSHFPVGAALLTQEGRIFKGCNIENACYPLGICAERTAIQKAVSEGYKDFRAIAIASDMQDDFISPCGACRQVMREFGTNWPVYMTKPDGTYIVMTVQELLPSSFGPEDLQKTQ
Open
Disease
Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
1 +
Discontinued Drug
0

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Detailed Information

The CDA (Cytidine Deaminase) gene is located on the short arm of human chromosome 1 at position 1p35.3. It encodes a zinc-dependent enzyme with a molecular weight of approximately 16 kDa. Belonging to the cytidine/deoxycytidine deaminase family, the enzyme's active site features a highly conserved His-X-Glu-X(23–26)-Pro-Cys-X(2–4)-Cys motif, which coordinates a zinc ion essential for its catalytic activity.

CDA is highly expressed in several metabolically active tissues, notably the liver, bone marrow, and lymphatic organs. Its primary physiological function is to catalyze the deamination of cytidine and deoxycytidine into uridine and deoxyuridine, respectively, playing a pivotal role in the pyrimidine salvage pathway that maintains nucleotide homeostasis.

Genetic Polymorphisms and Functional Relevance

Extensive research has identified multiple functional single nucleotide polymorphisms (SNPs) in the CDA gene. Among these, A79C (rs2072671) and G208A (rs60369023) are most commonly studied and have been shown to significantly impact enzyme activity. For instance, in patients with advanced non-small cell lung cancer (NSCLC), those carrying the A79C variant (genotypes AC or CC) exhibit notably lower objective response rates to gemcitabine chemotherapy—ranging from 6.7% to 20%—compared to 41.3% in patients with the wild-type AA genotype. These findings suggest that CDA polymorphisms may influence drug metabolism by altering enzymatic function, thereby modulating chemotherapeutic efficacy.

Biological Functions and Pathological Mechanisms

In pancreatic ductal adenocarcinoma (PDAC), elevated CDA expression has been associated with resistance to immune checkpoint blockade. Mechanistically, this resistance is driven by the accumulation of a key metabolic byproduct—uridine diphosphate (UDP). UDP functions as a signaling molecule, binding to P2Y6 receptors on tumor-associated macrophages (TAMs), thereby inducing their polarization towards an immunosuppressive M2 phenotype. These M2 macrophages secrete anti-inflammatory cytokines such as TGF-β and IL-10, which suppress CD+T cell infiltration and promote the expansion of regulatory T cells (Tregs). The end result is the formation of an immune-evasive tumor microenvironment. Clinical analyses indicate that CDA mRNA levels in PDAC tissues are approximately 4.5 times higher than in adjacent normal tissues, with a corresponding 68% reduction in T-cell infiltration density.

Mechanisms of Chemoresistance

CDA also plays a critical role in mediating resistance to nucleoside analog-based chemotherapy. By catalyzing the deamination of drugs such as gemcitabine, CDA converts them into inactive metabolites, diminishing therapeutic efficacy. This enzymatic activity is particularly enhanced in tumors harboring the A79C polymorphism, where conformational changes in the enzyme lead to increased substrate binding affinity and accelerated drug inactivation.

Furthermore, CDA may influence cancer progression via epigenetic mechanisms. Loss-of-function or knockout of the CDA gene has been associated with global DNA hypomethylation, potentially leading to aberrant expression of oncogenes and further contributing to tumorigenesis.

Clinical Implications and Translational Advances

• Enhancing Immunotherapy Response

In preclinical PDAC mouse models, CDA knockout in combination with anti-PD-1 therapy resulted in a 72% reduction in tumor volume and a 2.3-fold extension in median survival. Mechanistic studies showed that CDA inhibition shifted the TAM population from M2 to M1 phenotype, increasing the M1/M2 ratio from 0.3 to 1.8 and enhancing CD8+ T cell infiltration into the tumor microenvironment.

• Optimizing Chemotherapy Efficacy

Genotype-guided dose adjustment has shown promise in improving gemcitabine treatment outcomes for NSCLC patients. Clinical data suggest that reducing the gemcitabine dose by 25% in patients carrying the A79C variant significantly decreases the incidence of severe neutropenia from 48% to 15%, while paradoxically improving the objective response rate to 28%.

• Development of Small Molecule Inhibitors

Tetrahydrouridine (THU) is a well-characterized competitive inhibitor of CDA that has shown the ability to significantly enhance the pharmacokinetics of gemcitabine. In melanoma models, co-administration of THU increased the area under the curve (AUC) of gemcitabine by 3.1-fold. THU is currently under investigation in Phase I/II clinical trials for its potential to potentiate nucleoside-based chemotherapy.

Challenges and Future Directions

Despite its therapeutic promise, targeting CDA presents several challenges—most notably, tissue-specific toxicity. Given CDA’s involvement in systemic pyrimidine metabolism, its broad inhibition may result in unintended side effects such as myelosuppression and hepatotoxicity.

To overcome these limitations, several strategies are under development:

  • Tumor-targeted delivery systems, such as lipid nanoparticle-encapsulated CDA siRNA, aim to selectively suppress CDA expression in tumors while sparing healthy tissues.
  • Bifunctional inhibitors, including CDA–PD-L1 bispecific antibodies, are being explored to simultaneously block CDA activity and immune checkpoint pathways.
  • Additionally, metabolic compensation following CDA inhibition is a potential concern. Upregulation of uridine phosphorylase may restore uridine biosynthesis and mitigate the effects of CDA knockdown. Therefore, combinatorial approaches using UP inhibitors may offer a promising route to circumvent this compensatory mechanism.

Looking ahead, CDA is emerging as a potential pan-cancer biomarker of immune resistance, with mechanistic relevance extending beyond PDAC to malignancies such as colorectal cancer and melanoma. Continued investigation into its immunometabolic functions could inform novel strategies for precision oncology.

Reference

  1. Rios LAS, Cloete B, Mowla S. Activation-induced cytidine deaminase: in sickness and in health. J Cancer Res Clin Oncol. 2020 Nov;146(11):2721-2730.

  2. Çakan E, Gunaydin G. Activation induced cytidine deaminase: An old friend with new faces. Front Immunol. 2022 Oct 27;13:965312.

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