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Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059017/ https://www.ncbi.nlm.nih.gov/pubmed/31950591 http://dx.doi.org/10.15252/emmm.201910419 |
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author | Rudd, Sean G Tsesmetzis, Nikolaos Sanjiv, Kumar Paulin, Cynthia BJ Sandhow, Lakshmi Kutzner, Juliane Hed Myrberg, Ida Bunten, Sarah S Axelsson, Hanna Zhang, Si Min Rasti, Azita Mäkelä, Petri Coggins, Si'Ana A Tao, Sijia Suman, Sharda Branca, Rui M Mermelekas, Georgios Wiita, Elisée Lee, Sun Walfridsson, Julian Schinazi, Raymond F Kim, Baek Lehtiö, Janne Rassidakis, Georgios Z Pokrovskaja Tamm, Katja Warpman‐Berglund, Ulrika Heyman, Mats Grandér, Dan Lehmann, Sören Lundbäck, Thomas Qian, Hong Henter, Jan‐Inge Schaller, Torsten Helleday, Thomas Herold, Nikolas |
author_facet | Rudd, Sean G Tsesmetzis, Nikolaos Sanjiv, Kumar Paulin, Cynthia BJ Sandhow, Lakshmi Kutzner, Juliane Hed Myrberg, Ida Bunten, Sarah S Axelsson, Hanna Zhang, Si Min Rasti, Azita Mäkelä, Petri Coggins, Si'Ana A Tao, Sijia Suman, Sharda Branca, Rui M Mermelekas, Georgios Wiita, Elisée Lee, Sun Walfridsson, Julian Schinazi, Raymond F Kim, Baek Lehtiö, Janne Rassidakis, Georgios Z Pokrovskaja Tamm, Katja Warpman‐Berglund, Ulrika Heyman, Mats Grandér, Dan Lehmann, Sören Lundbäck, Thomas Qian, Hong Henter, Jan‐Inge Schaller, Torsten Helleday, Thomas Herold, Nikolas |
author_sort | Rudd, Sean G |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7059017 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70590172020-03-11 Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy Rudd, Sean G Tsesmetzis, Nikolaos Sanjiv, Kumar Paulin, Cynthia BJ Sandhow, Lakshmi Kutzner, Juliane Hed Myrberg, Ida Bunten, Sarah S Axelsson, Hanna Zhang, Si Min Rasti, Azita Mäkelä, Petri Coggins, Si'Ana A Tao, Sijia Suman, Sharda Branca, Rui M Mermelekas, Georgios Wiita, Elisée Lee, Sun Walfridsson, Julian Schinazi, Raymond F Kim, Baek Lehtiö, Janne Rassidakis, Georgios Z Pokrovskaja Tamm, Katja Warpman‐Berglund, Ulrika Heyman, Mats Grandér, Dan Lehmann, Sören Lundbäck, Thomas Qian, Hong Henter, Jan‐Inge Schaller, Torsten Helleday, Thomas Herold, Nikolas EMBO Mol Med Articles 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. John Wiley and Sons Inc. 2020-01-17 2020-03-06 /pmc/articles/PMC7059017/ /pubmed/31950591 http://dx.doi.org/10.15252/emmm.201910419 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Rudd, Sean G Tsesmetzis, Nikolaos Sanjiv, Kumar Paulin, Cynthia BJ Sandhow, Lakshmi Kutzner, Juliane Hed Myrberg, Ida Bunten, Sarah S Axelsson, Hanna Zhang, Si Min Rasti, Azita Mäkelä, Petri Coggins, Si'Ana A Tao, Sijia Suman, Sharda Branca, Rui M Mermelekas, Georgios Wiita, Elisée Lee, Sun Walfridsson, Julian Schinazi, Raymond F Kim, Baek Lehtiö, Janne Rassidakis, Georgios Z Pokrovskaja Tamm, Katja Warpman‐Berglund, Ulrika Heyman, Mats Grandér, Dan Lehmann, Sören Lundbäck, Thomas Qian, Hong Henter, Jan‐Inge Schaller, Torsten Helleday, Thomas Herold, Nikolas Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
title | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
title_full | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
title_fullStr | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
title_full_unstemmed | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
title_short | Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy |
title_sort | ribonucleotide reductase inhibitors suppress samhd1 ara‐ctpase activity enhancing cytarabine efficacy |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059017/ https://www.ncbi.nlm.nih.gov/pubmed/31950591 http://dx.doi.org/10.15252/emmm.201910419 |
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