Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication

Abstract

Co-targeting of both de novo and salvage pathways for dCTP biosynthesis shows efficacy in T-ALL and B-ALL.

Human Biodistribution and Radiation Dosimetry of 18F-Clofarabine, a PET Probe Targeting the Deoxyribonucleoside Salvage Pathway

“…However, dCK is required for normal hematopoiesis (4) and DNA damage response (5). Moreover, dCK provides an escape mechanism when DNA de novo synthesis is inhibited by ribonucleotide reductase inhibitors (6). This resistance can be overcome using small-molecule inhibitors of dCK (6)(7)(8)(9).…”

“…Moreover, dCK provides an escape mechanism when DNA de novo synthesis is inhibited by ribonucleotide reductase inhibitors (6). This resistance can be overcome using small-molecule inhibitors of dCK (6)(7)(8)(9). dCK is also required to phosphorylate and activate inactive prodrugs such as cytarabine, gemcitabine, decitabine, and cladribine (10).…”

“…dCK is also required to phosphorylate and activate inactive prodrugs such as cytarabine, gemcitabine, decitabine, and cladribine (10). Therefore, a PET probe that specifically measures tissue dCK expression could serve as a predictive biomarker for tumor responses to dCK-dependent prodrugs, stratify patients into likely responders to small-molecule dCK inhibitors, and demonstrate target engagement in patients treated with dCK inhibitors (6).…”

Harnessing Preclinical Molecular Imaging to Inform Advances in Personalized Cancer Medicine

“…To accommodate this demand, cells can produce dNTPs either de novo from metabolic precursors, including glucose and glutamine, or by salvaging deoxynucleosides from the extracellular milieu (47). Although still incompletely understood, it is likely that malignant cells favor de novo dNTP synthesis over salvage but can switch between the two for DNA replication, depending on environmental factors (48).…”

Replication stress and cancer: It takes two to tango

“…However, it is important to note that cells not only synthesize nucleotides but can also scavenge them from the environment. In fact, a recent study revealed that the efficiency of chemotherapeutic strategies targeting nucleotide biosynthesis is greatly enhanced by simultaneously targeting the nucleotide savage pathway [102]. The need of cancer cells to maintain a healthy pool of dNTPs is highlighted by the recent discovery of inhibitors of the MTH1 enzyme, responsible for sanitizing oxidized nucleotides in the cells.…”