IMPDH inhibition enhances cytarabine efficacy in SAMHD1 ‐expressing leukaemia cells via guanine nucleotide depletion

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.