Increase of PRPP enhances chemosensitivity of PRPS1 mutant acute lymphoblastic leukemia cells to 5‐Fluorouracil

Abstract

Relapse‐specific mutations in phosphoribosyl pyrophosphate synthetase 1 (PRPS1), a rate‐limiting purine biosynthesis enzyme, confer significant drug resistances to combination chemotherapy in acute lymphoblastic leukemia (ALL). It is of particular interest to identify drugs to overcome these resistances. In this study, we found that PRPS1 mutant ALL cells specifically showed more chemosensitivity to 5‐Fluorouracil (5‐FU) than control cells, attributed to increased apoptosis of PRPS1 mutant cells by 5‐FU. Mechanistically, PRPS1 mutants increase the level of intracellular phosphoribosyl pyrophosphate (PRPP), which causes the apt conversion of 5‐FU to FUMP and FUTP in Reh cells, to promote 5‐FU‐induced DNA damage and apoptosis. Our study not only provides mechanistic rationale for re‐targeting drug resistant cells in ALL, but also implicates that ALL patients who harbor relapse‐specific mutations of PRPS1 might benefit from 5‐FU‐based chemotherapy in clinical settings.

Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia

“…Relapsed ALL prognosis is dismal and developing strategies to treat these patients is of utmost importance. In this regard, NT5C2 and PRPS1 rise as promising therapeutic targets [ 97 , 100 ].…”

“…Gain-of-function mutations and increased levels of PRPS1 could also facilitate the conversion of 5‐Fluorouracil (5‐FU) (a pyrimidine analog used for several types of cancers) to their active metabolites (fluorodeoxyuridine monophosphate, fluorodeoxyuridine triphosphate and fluorouridine triphosphate), subsequently triggering genomic damage and apoptosis [113] . Therefore, ALL patients who carry activating mutations could benefit from 5-FU administration during therapy [100] . Whole exome sequencing analysis revealed PRPS1 mutations in 2.7% and 13% of relapsed B-ALL cases from Germany and China, respectively, being p.Ala190Thr and p.Ser103Thr the most common.…”

5-Fluorouracil in combination with deoxyribonucleosides and deoxyribose as possible therapeutic options for the Coronavirus, COVID-19 infection

“…Finally it should be noted that 5-FU has been in use for a long time to treat certain cancers such as colorectal cancer [23,24], in pancreatic cancer [25], head and neck cancer [26], lymphoblastic leukaemia [27] and acute myeloid leukaemia [28]. According to results of a recent search of PubMed no less than 50,340 research papers have been published on this compound and hence this agent may be considered relatively safe when applied to SASRS-CoV-2 infected patients.…”

PRPS-Associated Disorders and the Drosophila Model of Arts Syndrome

“…These mutations make cancer cells favor de novo nucleotide synthesis and become less sensitive to the drugs whose efficacy depends on the purine salvage pathway [ 30 ]. Interestingly, a study also showed that cell lines with a relapse-specific PRPS1 mutation become hypersensitive to 5-fluorouracil (5-FU), an antimetabolite drug that targets de novo pyrimidine biosynthesis [ 32 ]. This study supports the notion that the growth and survival of thiopurine-resistant cancer cells largely depend on de novo nucleotide biosynthesis.…”