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

• Type of Material: Article
• Authors: Sean G. Rudd, Karolinska Institutet; Nikolaos Tsesmetzis, Karolinska Institutet; Kumar Sanjiv, Karolinska Institutet; Cynthia B. J. Paulin, Karolinska Institutet; Lakshmi Sandhow, Karolinska University Hospital; Juliane Kutzner, University Hospital Heidelberg; Ida Hed Myrberg, Karolinska Institutet; Sarah S. Bunten, University Hospital Heidelberg; Hanna Axelsson, Karolinska Institutet; Si Min Zhang, Karolinska Institutet; Azita Rasti, Karolinska Institutet; Petri Makela, Karolinska Institutet; Si'Ana A. Coggins, Emory University; Sijia Tao, Emory University; Sharda Suman, Karolinska Institutet; Rui M. Branca, Karolinska Institutet; Georgios Mermelekas, Karolinska Institutet; Elisee Wiita, Karolinska Institutet; Sun Lee, Karolinska Institutet; Julian Walfridsson, Karolinska University Hospital; Raymond Schinazi, Emory University; Baek Kim, Emory University; Janne Lehtio, Karolinska Institutet; Georgios Z. Rassidakis, Karolinska Institutet; Katja Pokrovskaja Tamm, Karolinska Institutet; Ulrika Warpman-Berglund, Karolinska Institutet; Mats Heyman, Karolinska Institutet; Dan Grander, Karolinska Institutet; Soren Lehmann, Karolinska University Hospital; Thomas Lundback, Karolinska Institutet; Hong Qian, Karolinska University Hospital; Jan-Inge Henter, Karolinska Institutet; Torsten Schaller, University Hospital Heidelberg; Thomas Helleday, Karolinska Institutet; Nikolas Herold, Karolinska Institutet
• Language: English
• Date: 2020-03-06
• Publisher: EMBO Press
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.15252/emmm.201910419
• Title of Journal or Parent Work: EMBO: Molecular Medicine
• Volume: 12
• Issue: 3
• Start Page: e10419
• End Page: e10419
• Grant/Funding Information: ìShizu Matsumuraî donation (2018‐01086 to N.H.); Swedish Research Council (2018‐02114 to S.G.R.; 2015‐02498 to Sö.L.; 2011‐3897 to J.‐I.H., and 2012‐5935, 2013‐3791 and 2015‐00162 to T.H.); This work was supported by grants from the Swedish Children's Cancer Foundation (TJ2017‐0021 (to S.G.R.); FR2017‐0154 (to H.Q.) PR2017‐0113 (to K.P.T.); PROF06/001, PR2015/005 and KP2018‐0005 (to J.‐I.H); PR2013‐0002 and PR2014‐0048 (to T.H.); TJ2016‐0040, PR2016‐0044 and PR2018‐0016 (to N.H.)); Torsten and Ragnar Söderberg Foundation (to T.H.); Swedish Medical Association (SLS‐875361 to N.H.); Karolinska Institutet Foundations (2016‐50273 & 2018‐01573 to S.G.R.; and 2016‐50756 & 2018‐01086 to N.H.); Lars Hierta Memorial Foundation (FO2018‐0002 to N.H.); Swedish Cancer Society (19‐0056‐JIA to S.G.R.; CAN 2017/774 to H.Q.; CAN 2014/814 to Sö.L.; CAN 2012/770 and CAN 2015/255 to T.H.; CAN 2013/396 and CAN 2016/275 to J.‐I.H.; and CAN 2017/517 to N.H.); J.K. was supported by the German Research Foundation (SCHA1950/1‐1).; Märta and Gunnar V Philipsons Foundation (to J.‐I.H. and N.H.); Radiumhemmet's Research Foundations (171162 to H.Q.; 154242 to G.R.; 174122 to D.G. and 191112 to N.H.); The Loo and Hans Osterman Foundation for Medical Research (2019‐01128 to S.G.R.); Chemical Biology Consortium Sweden is funded by the Swedish Research Council, Science for Life Laboratories and Karolinska Institutet (829‐2009‐6241 to H.A. and T.L.).; Harald och Greta Jeanssons Foundation (2018 and 2019 to N.H.); Sigurd och Elsa Goljes Memorial Foundation (LA2018‐0038 to N.H.); Mary Béve Foundation for childhood cancer research (to N.H.); Stockholm County Council (ALF; 20150353 to Sö.L.; 20150016 and 20180318 to J.‐I.H.; and K2892‐2016 to N.H); Clas Groschinsky Memorial Foundation (M18228 to N.H.); Alex and Eva Wallström Foundation for scientific research and education (2017‐00475 and 2018‐00109 to S.G.R.); This work was further supported by the National Institute of Health (AI136581 and GM104198 to B.K.; MH116695 to R.F.S.).; Felix Mindus contribution to Leukemia Research (2016‐52575, 2017‐01287, 2018‐02716 to S.G.R.; 2018‐02715 to N.H.; 2019‐02004 to S.M.Z.); Åke Wiberg Foundation (M18‐0012 to N.H.)
• Keywords: Acute Myeloid Leukemia; Cell-lines; SAMHD1; Triphosphohydrolase Activity; Synergistic interaction; Cytosine-Arabinoside; High-dose cytarabine; Research & Experimental Medicine; In-vitro; Science & Technology; Acute myeloid leukaemia; Enzyme-coupled assay; Life Sciences & Biomedicine; Allosteric activation; 1 Beta-D-Arabinofuranosylcystosine Metabolism; Chemotherapy resistance; Precision medicine; Medicine, Research & Experimental; Drug synergy
• Research Categories: Health Sciences, Pathology; Biology, Virology; Health Sciences, Oncology; Health Sciences, Medicine and Surgery

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.