Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy.

Sean G Rudd ,Dan Grandér,Lakshmi Sandhow,Baek Kim,Hong Qian,Julian Walfridsson,Juliane Kutzner,Sarah S Bunten,Kumar Sanjiv,Si Min Zhang,Torsten Schaller,Sören Lehmann,Mats Heyman,Azita Rasti,Thomas Helleday,Elisée Wiita,Katja Pokrovskaja Tamm,Thomas Lundbäck,Hanna Axelsson,Sijia Tao,Georgios Mermelekas,Ida Hed Myrberg,Nikolas Herold,Nikolaos Tsesmetzis,Janne Lehtiö,Sun Lee,Petri Mäkelä,Sharda Suman,Jan‐Inge Henter,Georgios Z Rassidakis ,Rui M Branca ,Ulrika Warpman Berglund ,Raymond F Schinazi ,Cynthia B.j Paulin ,Si’ana A Coggins

doi:10.15252/emmm.201910419

Abstract

The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.

Highlights

Five-year overall survival (OS) in acute myeloid leukaemia (AML) varies with age, ranging from ~ 5% in elderly adults to more than 70% in children, causing more than 10,000 deaths yearly in the United States alone
Clinical responses to ara-C correlate with accumulation of the active metabolite ara-CTP in AML cells (Plunkett et al, 1985), which is strongly regulated by the dNTPase SAM and HD domain-containing protein-1 (SAMHD1) (Schneider et al, 2016; Herold et al, 2017a,b,c; Hollenbaugh et al, 2017; Rudd et al, 2017; Rassidakis et al, 2018)
We further demonstrate that these effects are restricted to non-allosteric RNR inhibitors (RNRi) inhibitors as known allosteric inhibitors Cl-F-ara-A, F-ara-A and 2-CdA did not display SAMHD1-dependent synergy with ara-C

Summary

Introduction

Five-year overall survival (OS) in AML varies with age, ranging from ~ 5% in elderly adults to more than 70% in children, causing more than 10,000 deaths yearly in the United States alone Standard chemotherapy in AML treatment comprises anthracyclines, which are important for the achievement of complete remission during induction courses (Fernandez et al, 2009; Luskin et al, 2016), and the deoxycytidine analogue cytarabine (ara-C). The latter constitutes the backbone of high-dose remission consolidation therapy (Mayer et al, 1994; Lowenberg, 2013). The interpatient susceptibility to high-dose ara-C regimens is linked to the propensity of AML blasts to accumulate the active triphosphate metabolite ara-CTP (Plunkett et al, 1985), which causes DNA damage by perturbing DNA synthesis (Tsesmetzis et al, 2018). Inactivation of SAMHD1 is a prime goal for rational improvement of ara-C-based therapies; no valid clinical strategies exist, nor are known efforts under development (Appendix Table S1)

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Conclusion