Re-Discovery of Pyrimidine Salvage as Target in Cancer Therapy

Abstract

Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids and glucose, the salvage pathway recovers nucleosides or bases formed during DNA or RNA degradation. In contrast to high proliferating non-malignant cells, which are highly dependent on the de novo synthesis, cancer cells can switch to the nucleoside salvage pathways to maintain efficient DNA replication. Pyrimidine de novo synthesis remains the target of interest in cancer therapy and several inhibitors showed promising results in cancer cells and in vivo models. In the 1980s and 1990s, poor responses were however observed in clinical trials with several of the currently existing pyrimidine synthesis inhibitors. To overcome the observed limitations in clinical trials, targeting pyrimidine salvage alone or in combination with pyrimidine de novo inhibitors was suggested. Even though this approach showed initially promising results, it received fresh attention only recently. Here we discuss the re-discovery of targeting pyrimidine salvage pathways for DNA replication alone or in combination with inhibitors of pyrimidine de novo synthesis to overcome limitations of commonly used antimetabolites in various preclinical cancer models and clinical trials. We also highlight newly emerged targets in pyrimidine synthesis as well as pyrimidine salvage as a promising target in immunotherapy.

Characterization of uridine-cytidine kinase like-1 nucleoside kinase activity and its role in tumor growth

“…This includes genes that regulate both the pyrimidine de novo and salvage pathways. More than two decades ago, inhibitors of de novo pyrimidine synthesis were developed for potential use in cancer therapy [ 31 ]. Pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which is the fourth of six universally conserved enzymatic reactions in the pyrimidine de novo synthetic pathway, was reported to reduce liver metastasis in colorectal cancer and small cell lung cancer models [ 32–34 ].…”

“…DHODH inhibitors significantly decreased levels of leukemia-initiating cells, and improved survival of leukemia-bearing mice [ 35 ]. It was soon discovered that cancer cells could escape the de novo synthesis pathway and adapt the nucleotide salvage pathway for DNA replication and cell proliferation [ 31 ]. Researchers turned their focus to the salvage pathway for targeted cancer treatment, but eventually this was set aside because of limitations translating in vitro studies into in vivo and clinical studies [ 31 ].…”

“…It was soon discovered that cancer cells could escape the de novo synthesis pathway and adapt the nucleotide salvage pathway for DNA replication and cell proliferation [ 31 ]. Researchers turned their focus to the salvage pathway for targeted cancer treatment, but eventually this was set aside because of limitations translating in vitro studies into in vivo and clinical studies [ 31 ]. In the last few years, there has been a reemergence of interest in targeting the pyrimidine salvage pathway due to the development of new inhibitors [ 31 ].…”

“…Researchers turned their focus to the salvage pathway for targeted cancer treatment, but eventually this was set aside because of limitations translating in vitro studies into in vivo and clinical studies [ 31 ]. In the last few years, there has been a reemergence of interest in targeting the pyrimidine salvage pathway due to the development of new inhibitors [ 31 ]. Sarkisjan et al found that the novel cytidine analog fluorocyclopentenylcytosine (RX-3117) is activated by UCK2 only.…”

Targeting the DNA damage response and repair in cancer through nucleotide metabolism

“…Here, we have discussed just two targets, which can be exploited to induce DNA damage in cancer cells, MTH1 and MTHFD2; however, there are many more. Nucleotide biosynthesis has been considered a nononcogene addiction of cancer cells, as dNTPs are required to fuel cancer cell proliferation, and accordingly, many of the enzymes in these pathways have been revisited time and time again in the context of cancer therapy [ 169 ]. However, given dNTP biosynthesis is unquestionably important for all dividing cells, caution should be applied when targeting potential pan‐essential genes [ 170 ].…”