IMPDH inhibition enhances cytarabine efficacy in SAMHD1 ‐expressing leukaemia cells via guanine nucleotide depletion
Year: 2026
Type: article
Abstract: The nucleoside analogue cytarabine (ara-C) is part of standard treatment against acute myeloid leukaemia (AML). The efficacy of this therapy is dependent upon accumulation of the active triphosphate metabolite ara-CTP, which mis-incorporates into genomic DNA, triggering cell death. The deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) SAMHD1 can hydrolyse ara-CTP and thereby convert the active metabolite back to its inactive prodrug form. This constitutes a barrier to treatment efficacy and thus strategies to target SAMHD1 are warranted. SAMHD1 activity is allosterically regulated by nucleotides, which are synthesised in cells via distinct pathways. We screened a collection of drugs targeting nucleotide biosynthetic enzymes and identified that inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH), responsible for catalysing the rate-limiting step in guanine nucleotide biosynthesis, sensitises AML cell lines to ara-C in a SAMHD1-dependent manner. We show that approved drugs inhibiting IMPDH-mycophenolic acid and ribavirin-imbalance deoxyribonucleoside triphosphate pools and increase ara-C efficacy in SAMHD1-proficient, but not deficient, leukaemic cells. Altogether, we provide insight into SAMHD1 regulation in leukaemic cells and show how this process can be exploited by approved drugs to improve ara-C therapy.
Source: Molecular Oncology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,300
Funders: Åke Wiberg Stiftelse, Loo och Hans Ostermans Stiftelse för Medicinsk Forskning, Japan Chemical Industry Association, European Commission, Cancerfonden, Fondation pour la Recherche Médicale, Svenska Sällskapet för Medicinsk Forskning, Karolinska Institutet, Vetenskapsrådet, Stiftelsen Lars Hiertas Minne, Barncancerfonden, Stiftelsen Clas Groschinskys Minnesfond, Science for Life Laboratory, Dr Åke Olssons Stiftelse för Haematologisk Forskning, Stiftelsen Felix Mindus Bidrag till Leukemiforskningen, National Cancer Institute, HORIZON EUROPE Marie Sklodowska-Curie Actions
Awards: G1044278454, Longitudinal profiling of the aging plasma proteome to identify risk and resilience profiles in neurocognitive aging, G1147202773, Att övervinna läkemedelsresistens vid akuta leukemier med SAMHD1-hämmare, G1679472736, G1684405982, G1896045634, G2076215548, G212670385, G224898004, G2409199353, G2508547524, Effektivare kemoterapi för leukemidrabbade, G2804011866, G2994895028, FCAECC Fellowship programme for talented researchers in cancer, G3655759448, Med SAMHD1 enzymet i sikte kunna förbättra behandlingen av hematologiska maligniteter hos barn, G4305857609, Targeting SAMHD1 to enhance existing cancer therapies, G5099344984, G532187110, G5559080118, G6008190857, G6969285288, G712881263, G7543015574, G7635377842, G7799207878, G817980260
OpenAlex ID: W7130513280