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EMBO Mol Med. 2020 Jan 17:e10419. doi: 10.15252/emmm.201910419. [Epub ahead of print]

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

Author information

1
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
2
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
3
Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
4
Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
5
Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
6
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
7
Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
8
Department of Pharmacy, Kyung-Hee University, Seoul, South Korea.
9
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
10
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
11
Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
12
Paediatric Oncology, Theme of Children's Health, Karolinska University Hospital Solna, Stockholm, Sweden.
13
Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

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:

SAMHD1; acute myeloid leukaemia; chemotherapy resistance; drug synergy; precision medicine

PMID:
31950591
DOI:
10.15252/emmm.201910419
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