Ribonucleoside-diphosphate reductase (RR) and Eukaryotic translation initiation factor 2-alpha kinase 2 (PKR) (RR / PKR)

This target profile describes a specific cellular environment found in many malignancies, characterized by elevated ribonucleotide reductase (RR) activity and impaired Protein Kinase R (PKR) signaling (NIH, 2023). Ribonucleotide reductase is a rate-limiting enzyme responsible for converting ribonucleotides into deoxyribonucleotides, which are essential for DNA synthesis and repair; its upregulation in tumor cells supports rapid proliferation (PubMed: 10444016). The PKR pathway is a critical component of the innate immune system that detects double-stranded RNA and halts protein translation to prevent viral replication (UniProt: P19544). In many cancers, this pathway is suppressed—often through the activation of the Ras signaling pathway—to allow for uninterrupted growth (PubMed: 9843496). Therapeutic strategies, particularly oncolytic virotherapy, exploit these vulnerabilities for tumor-selective targeting. For instance, engineered Herpes Simplex Virus (HSV) mutants like G207 are designed with deletions in the viral RR gene (ICP6) and the PKR-evasion gene (gamma34.5) (PubMed: 10637341). These modifications restrict viral replication to cells that can compensate for the missing viral functions: those with high endogenous RR levels and defective PKR-mediated translation inhibition. This approach ensures that the virus selectively lyses tumor cells while sparing healthy tissue, simultaneously triggering a systemic anti-tumor immune response through the release of tumor-associated antigens and inflammatory cytokines (PubMed: 26515559).

Other names

Ribonucleotide reductaseProtein kinase REIF2AK2RRM1RRM2PKR pathwayRas-activated tumor cellsICP6/gamma34.5-deleted HSV targets

Oncolytic viruses selectively replicate in cells with high ribonucleotide reductase activity and/or PKR pathway defects, leading to cell lysis and induction of anti-tumor immunity. Small molecule inhibitors of ribonucleotide reductase block DNA synthesis by depleting deoxyribonucleotide pools.