EMBO Molecular Medicine (Mar 2020)
Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy
- Sean G Rudd,
- Nikolaos Tsesmetzis,
- Kumar Sanjiv,
- Cynthia BJ Paulin,
- Lakshmi Sandhow,
- Juliane Kutzner,
- Ida Hed Myrberg,
- Sarah S Bunten,
- Hanna Axelsson,
- Si Min Zhang,
- Azita Rasti,
- Petri Mäkelä,
- Si'Ana A Coggins,
- Sijia Tao,
- Sharda Suman,
- Rui M Branca,
- Georgios Mermelekas,
- Elisée Wiita,
- Sun Lee,
- Julian Walfridsson,
- Raymond F Schinazi,
- Baek Kim,
- Janne Lehtiö,
- Georgios Z Rassidakis,
- Katja Pokrovskaja Tamm,
- Ulrika Warpman‐Berglund,
- Mats Heyman,
- Dan Grandér,
- Sören Lehmann,
- Thomas Lundbäck,
- Hong Qian,
- Jan‐Inge Henter,
- Torsten Schaller,
- Thomas Helleday,
- Nikolas Herold
Affiliations
- Sean G Rudd
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Nikolaos Tsesmetzis
- Childhood Cancer Research Unit Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Kumar Sanjiv
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Cynthia BJ Paulin
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Lakshmi Sandhow
- Center for Hematology and Regenerative Medicine Department of Medicine Karolinska University Hospital Huddinge Karolinska Institutet Stockholm Sweden
- Juliane Kutzner
- Department of Infectious Diseases Virology University Hospital Heidelberg Heidelberg Germany
- Ida Hed Myrberg
- Childhood Cancer Research Unit Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Sarah S Bunten
- Department of Infectious Diseases Virology University Hospital Heidelberg Heidelberg Germany
- Hanna Axelsson
- Chemical Biology Consortium Sweden Science for Life Laboratory Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm Sweden
- Si Min Zhang
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Azita Rasti
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Petri Mäkelä
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Si'Ana A Coggins
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Sijia Tao
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Sharda Suman
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Rui M Branca
- Department of Oncology‐Pathology Science for Life Laboratory Karolinska Institutet Stockholm Sweden
- Georgios Mermelekas
- Department of Oncology‐Pathology Science for Life Laboratory Karolinska Institutet Stockholm Sweden
- Elisée Wiita
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Sun Lee
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Julian Walfridsson
- Center for Hematology and Regenerative Medicine Department of Medicine Karolinska University Hospital Huddinge Karolinska Institutet Stockholm Sweden
- Raymond F Schinazi
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Baek Kim
- Department of Pediatrics Emory University School of Medicine Atlanta GA USA
- Janne Lehtiö
- Department of Oncology‐Pathology Science for Life Laboratory Karolinska Institutet Stockholm Sweden
- Georgios Z Rassidakis
- Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Katja Pokrovskaja Tamm
- Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Ulrika Warpman‐Berglund
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Mats Heyman
- Childhood Cancer Research Unit Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Dan Grandér
- Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Sören Lehmann
- Center for Hematology and Regenerative Medicine Department of Medicine Karolinska University Hospital Huddinge Karolinska Institutet Stockholm Sweden
- Thomas Lundbäck
- Chemical Biology Consortium Sweden Science for Life Laboratory Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm Sweden
- Hong Qian
- Center for Hematology and Regenerative Medicine Department of Medicine Karolinska University Hospital Huddinge Karolinska Institutet Stockholm Sweden
- Jan‐Inge Henter
- Childhood Cancer Research Unit Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Torsten Schaller
- Department of Infectious Diseases Virology University Hospital Heidelberg Heidelberg Germany
- Thomas Helleday
- Science for Life Laboratory Department of Oncology‐Pathology Karolinska Institutet Stockholm Sweden
- Nikolas Herold
- Childhood Cancer Research Unit Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- DOI
- https://doi.org/10.15252/emmm.201910419
- Journal volume & issue
-
Vol. 12,
no. 3
pp. n/a – n/a
Abstract
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.
Keywords