Work

Ribonucleotide Reductase Dysregulation in Cancer – Oncogenic Hijacking and Novel Therapies: Teaching an Old Dog New Tricks

Year: 2026

Type: review

Abstract: Ribonucleotide reductase (RNR) is the rate-limiting enzyme in deoxyribonucleotide synthesis and is therefore essential for DNA replication, repair, and cell-cycle progression. Because cancer cells rely heavily on nucleotide production to sustain proliferation and genome maintenance, RNR has long been an important therapeutic target. However, while several RNR inhibitors are clinically approved, their utility can be impacted by dose-limiting toxicities, poor pharmacokinetic and pharmacodynamic properties, and diverse mechanisms of therapeutic resistance. In this review, we examine emerging mechanisms that regulate RNR in cancer beyond canonical cell-cycle and DNA-damage pathways that could serve as additional targets for blocking RNR. We discuss subunit-specific transcriptional and epigenetic programs, post-translational modifications, protein-protein interactions, and signaling crosstalk that control RRM1, RRM2, and RRM2B expression and activity. We further highlight non-canonical functions of RNR subunits in PI3K/AKT, MAPK/ERK, immune, epithelial-to-mesenchymal transition (EMT), antioxidant, and ferroptosis pathways, emphasizing how these activities may contribute to tumor progression and drug resistance. We summarize mechanisms underlying resistance to conventional RNR inhibitors, including altered drug transport and metabolism, RNR overexpression, and acquisition of stem-like and EMT phenotypes with an emphasis on approaches to overcome these limitations. Lastly, we provide an in-depth summary of preclinical RNR inhibitors, highlighting how they compare to FDA-approved RNR inhibitors and their progression in clinical trials. Collectively, these advances underscore the role of RNR in tumorigenesis and identify opportunities to develop more selective and effective RNR-targeted therapies.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113710

Authors: Taylor L. Brzozowski, Mary C. Vincent, Ruth A. Keri

Institutions: Case Comprehensive Cancer Center, Cleveland Clinic Research, Case Western Reserve University, Cleveland Clinic Lerner College of Medicine

Language: English

Topic: Biochemical and Molecular Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,430