Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy.
SAMHD1
acute myeloid leukaemia
chemotherapy resistance
drug synergy
precision medicine
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
06 03 2020
06 03 2020
Historique:
received:
01
02
2019
revised:
15
12
2019
accepted:
17
12
2019
pubmed:
18
1
2020
medline:
29
7
2021
entrez:
18
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31950591
doi: 10.15252/emmm.201910419
pmc: PMC7059017
doi:
Substances chimiques
Cytarabine
04079A1RDZ
Arabinofuranosylcytosine Triphosphate
13191-15-6
Ribonucleotide Reductases
EC 1.17.4.-
SAM Domain and HD Domain-Containing Protein 1
EC 3.1.5.-
Samhd1 protein, mouse
EC 3.1.5.-
CTPase
EC 3.6.1.-
Pyrophosphatases
EC 3.6.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e10419Subventions
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ID : 20180318
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Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Ann Hematol. 1992 Jul;65(1):26-32
pubmed: 1643157
J Biol Chem. 2016 Oct 7;291(41):21407-21413
pubmed: 27566548
J Virol. 1998 Oct;72(10):7941-9
pubmed: 9733832
Nat Med. 2017 Feb;23(2):250-255
pubmed: 27991919
PLoS Pathog. 2015 Oct 02;11(10):e1005194
pubmed: 26431200
Proteins. 2019 Sep;87(9):748-759
pubmed: 31017331
Cancers (Basel). 2018 Jul 23;10(7):
pubmed: 30041457
Biochem Pharmacol. 1984 May 1;33(9):1515-8
pubmed: 6732868
Cancer Res. 1989 Dec 15;49(24 Pt 1):6923-8
pubmed: 2573423
Cell Growth Differ. 1994 Dec;5(12):1339-46
pubmed: 7696182
Proc Natl Acad Sci U S A. 2014 May 6;111(18):E1843-51
pubmed: 24753578
Leuk Res. 1996 Jan;20(1):37-45
pubmed: 8632676
Cancer Res. 2007 Dec 15;67(24):11648-56
pubmed: 18089794
J Biol Chem. 2011 Jul 15;286(28):25047-55
pubmed: 21454906
Anal Chem. 2010 Mar 1;82(5):1982-9
pubmed: 20143781
Int J Cancer. 2015 Mar 1;136(5):E359-86
pubmed: 25220842
Leukemia. 2001 Jan;15(1):69-73
pubmed: 11243402
Blood Cancer J. 2016 Jul 01;6(7):e441
pubmed: 27367478
Cancer Res. 1984 Aug;44(8):3286-90
pubmed: 6611198
J Biomol Screen. 2015 Jul;20(6):801-9
pubmed: 25755265
J Biol Chem. 2004 Dec 3;279(49):51545-53
pubmed: 15452123
Mol Immunol. 1994 Jun;31(9):643-9
pubmed: 8028598
Biochemistry. 1993 Nov 2;32(43):11569-74
pubmed: 8218224
Cancer Res. 1990 Jun 15;50(12):3675-80
pubmed: 2340517
Mol Cancer Ther. 2013 Dec;12(12):2675-84
pubmed: 24121103
Eur J Cancer. 1994;30A(3):417-8
pubmed: 8204374
Leuk Res. 1997 Sep;21(9):811-5
pubmed: 9393595
Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14324-9
pubmed: 17726094
Cancer Res. 1995 Apr 1;55(7):1517-24
pubmed: 7533664
J Biol Chem. 2014 Nov 21;289(47):32617-27
pubmed: 25288794
Klin Wochenschr. 1976 Mar 1;54(5):203-9
pubmed: 1062636
Cancer Res. 1996 Jul 1;56(13):3030-7
pubmed: 8674058
Biochemistry. 2018 Nov 27;57(47):6624-6636
pubmed: 30380297
J Am Chem Soc. 2014 Jul 16;136(28):9822-5
pubmed: 24983818
Nat Med. 2017 Feb;23(2):256-263
pubmed: 28067901
Blood. 1997 Jul 1;90(1):270-8
pubmed: 9207462
Antimicrob Agents Chemother. 2015 Jan;59(1):186-92
pubmed: 25331707
Nat Commun. 2018 Jan 17;9(1):250
pubmed: 29343827
Nat Commun. 2017 Aug 14;8(1):241
pubmed: 28808226
Semin Oncol. 1992 Jun;19(3 Suppl 9):1-10
pubmed: 1641648
Chemistry. 2007;13(30):8507-15
pubmed: 17636467
Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1513-6
pubmed: 15571288
Semin Oncol. 1985 Jun;12(2 Suppl 3):139-43
pubmed: 3859928
PLoS One. 2017 Jan 3;12(1):e0169052
pubmed: 28046007
EMBO Mol Med. 2020 Mar 6;12(3):e10419
pubmed: 31950591
Pharmacol Rev. 1989 Jun;41(2):93-141
pubmed: 2692037
Invest New Drugs. 2008 Jun;26(3):233-9
pubmed: 18217206
Semin Oncol. 1992 Jun;19(3 Suppl 9):84-9
pubmed: 1641659
Blood. 1991 Dec 1;78(11):2937-44
pubmed: 1954383
Comput Struct Biotechnol J. 2015 Sep 25;13:504-13
pubmed: 26949479
Mol Pharm. 2014 Dec 1;11(12):4395-404
pubmed: 25313982
Biochem Pharmacol. 2007 May 15;73(10):1548-57
pubmed: 17324380
Semin Oncol. 1985 Jun;12(2 Suppl 3):20-30
pubmed: 4012338
Future Oncol. 2005 Feb;1(1):7-17
pubmed: 16555971
PLoS One. 2014 Aug 07;9(8):e104125
pubmed: 25101980
Science. 2017 Nov 10;358(6364):797-802
pubmed: 29123070
Exp Hematol. 2017 Aug;52:32-39
pubmed: 28502830
Biochem Pharmacol. 1988 May 1;37(9):1745-9
pubmed: 2454114
Jpn J Cancer Res. 1985 Aug;76(8):729-35
pubmed: 3930450
Blood Adv. 2018 Jun 26;2(12):1480-1494
pubmed: 29945938
Eur J Cancer. 2015 Sep;51(14):2008-21
pubmed: 26188848
Cancer Res. 1980 Sep;40(9):3286-92
pubmed: 7427943
Int J Oncol. 2001 Jul;19(1):157-62
pubmed: 11408937
Antioxid Redox Signal. 2017 Dec 1;27(16):1317-1331
pubmed: 28398823
Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9815-20
pubmed: 21628579
Am J Hematol. 1995 May;49(1):48-55
pubmed: 7741138
Cancer Res. 1991 May 1;51(9):2386-94
pubmed: 1707752
J Pediatr Hematol Oncol. 2008 May;30(5):353-7
pubmed: 18458568
ACS Chem Biol. 2016 Jul 15;11(7):2021-32
pubmed: 27159113
N Engl J Med. 1994 Oct 6;331(14):896-903
pubmed: 8078551
Adv Exp Med Biol. 1998;431:249-53
pubmed: 9598069
Cell Cycle. 2017 Jun 3;16(11):1029-1038
pubmed: 28436707
Nature. 2011 May 25;474(7353):654-7
pubmed: 21613998
Pharmacogenomics. 2013 Sep;14(12):1449-66
pubmed: 24024897
J Biol Chem. 2000 Dec 15;275(50):39267-71
pubmed: 11006282
Adv Exp Med Biol. 1989;253B:363-7
pubmed: 2610124
J Biol Chem. 2015 May 22;290(21):13279-92
pubmed: 25847232
N Engl J Med. 2009 Sep 24;361(13):1249-59
pubmed: 19776406
Eur J Cancer. 1998 May;34(6):895-901
pubmed: 9797704
Blood. 2016 Mar 24;127(12):1551-8
pubmed: 26755712
Mol Cancer Ther. 2017 Dec;16(12):2645-2655
pubmed: 29203694
Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8333-7
pubmed: 7667290
Acta Crystallogr D Biol Crystallogr. 2015 Mar;71(Pt 3):516-24
pubmed: 25760601
Nat Struct Mol Biol. 2013 Nov;20(11):1304-9
pubmed: 24141705
Leuk Lymphoma. 2003 Jan;44(1):165-73
pubmed: 12691159
Sci Rep. 2016 Nov 15;6:37250
pubmed: 27845436
Nature. 2011 Jun 29;474(7353):658-61
pubmed: 21720370
Mol Cell Oncol. 2017 Feb 3;4(2):e1287554
pubmed: 28401188
J Biol Chem. 2012 Oct 12;287(42):35768-78
pubmed: 22915594
Med Pediatr Oncol. 1982;10 Suppl 1:81-91
pubmed: 6761570
Leuk Lymphoma. 2016 Oct;57(10):2281-8
pubmed: 26849624
Proc Natl Acad Sci U S A. 1981 Aug;78(8):5132-6
pubmed: 6975478
Blood. 2013 Jan 3;121(1):26-8
pubmed: 23287624
Cancer Res. 2016 Sep 15;76(18):5501-11
pubmed: 27530327
Am J Hematol. 1992 Nov;41(3):178-83
pubmed: 1415192
Biochemistry. 2016 Oct 4;55(39):5635-5646
pubmed: 27588835
Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10022-E10031
pubmed: 30305425
Hematology. 2004 Jun;9(3):223-33
pubmed: 15204104
Leuk Res. 2006 Jul;30(7):813-22
pubmed: 16478631
Blood Cancer J. 2018 Oct 19;8(11):98
pubmed: 30341277
J Clin Oncol. 1987 Mar;5(3):419-25
pubmed: 3819808
Cancer Res. 1983 Jun;43(6):2688-93
pubmed: 6189585
Cancer Res. 1978 Apr;38(4):978-89
pubmed: 205355
Clin Cancer Res. 2007 Jun 1;13(11):3380-7
pubmed: 17545546
Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8241-8246
pubmed: 28716944