AURKA and PLK1 inhibition selectively and synergistically block cell cycle progression in diffuse midline glioma.
Biological sciences
Cancer
Cell biology
Molecular biology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
17 Jun 2022
17 Jun 2022
Historique:
received:
25
10
2021
revised:
18
01
2022
accepted:
09
05
2022
entrez:
31
5
2022
pubmed:
1
6
2022
medline:
1
6
2022
Statut:
epublish
Résumé
Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. In this study, we show that Aurora kinase A (AURKA) is overexpressed in DMG and can be used as a therapeutic target. Additionally, AURKA inhibition combined with CRISPR/Cas9 screening in DMG cells, revealed polo-like kinase 1 (PLK1) as a synergistic target with AURKA. Using a panel of patient-derived DMG culture models, we demonstrate that treatment with volasertib, a clinically relevant and selective PLK1 inhibitor, synergizes with different AURKA inhibitors, supporting the CRISPR screen results. Mechanistically, our results show that combined loss of PLK1 and AURKA causes a G2/M cell cycle arrest which blocks vital parts of DNA-damage repair and induces apoptosis, solely in DMG cells. Altogether, our findings highlight the importance of AURKA and PLK1 for DMG propagation and demonstrate the potential of concurrently targeting these proteins as a therapeutic strategy for these devastating pediatric brain tumors.
Identifiants
pubmed: 35637734
doi: 10.1016/j.isci.2022.104398
pii: S2589-0042(22)00669-1
pmc: PMC9142558
doi:
Types de publication
Journal Article
Langues
eng
Pagination
104398Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
The authors have no conflicts of interest to declare.
Références
J Med Chem. 2011 Jan 13;54(1):312-9
pubmed: 21128645
Curr Neuropharmacol. 2017;15(1):88-97
pubmed: 27157264
Ann Neurol. 2015 Sep;78(3):355-74
pubmed: 26017892
Leukemia. 2015 Jan;29(1):11-9
pubmed: 25027517
Mol Cancer. 2021 Jan 15;20(1):15
pubmed: 33451333
Cell Mol Life Sci. 2018 Mar;75(5):871-887
pubmed: 29164272
Transl Oncol. 2015 Jun;8(3):185-95
pubmed: 26055176
BMC Cancer. 2012 Mar 05;12:80
pubmed: 22390279
Nat Genet. 2014 Jul;46(7):726-30
pubmed: 24880341
Oncogene. 2019 Sep;38(38):6479-6490
pubmed: 31324890
Cancers (Basel). 2019 May 13;11(5):
pubmed: 31086012
Clin Cancer Res. 2020 Jul 1;26(13):3319-3332
pubmed: 32165429
J Virol. 1998 Nov;72(11):8463-71
pubmed: 9765382
Oncotarget. 2017 Oct 19;8(57):97290-97303
pubmed: 29228610
Med Res Rev. 2016 Jul;36(4):749-86
pubmed: 27140825
Oncol Rep. 2016 Aug;36(2):819-26
pubmed: 27373675
Front Oncol. 2015 Dec 23;5:283
pubmed: 26779436
Exp Cell Res. 2017 Nov 15;360(2):397-403
pubmed: 28947132
Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15605-10
pubmed: 18832152
Am J Pathol. 2010 Aug;177(2):918-29
pubmed: 20581060
Bioinformatics. 2017 Aug 01;33(15):2413-2415
pubmed: 28379339
MethodsX. 2018 Feb 27;5:173-183
pubmed: 30622915
Methods Mol Biol. 2018;1712:203-216
pubmed: 29224076
J Clin Oncol. 2008 Jun 20;26(18):3015-24
pubmed: 18565887
Sci Signal. 2018 Aug 14;11(543):
pubmed: 30108183
Stem Cell Res. 2014 Jul;13(1):135-43
pubmed: 24879067
Cancer Res. 2009 Dec 1;69(23):9065-72
pubmed: 19920198
Oncotarget. 2015 Apr 20;6(11):9327-40
pubmed: 25871386
Acta Biochim Biophys Sin (Shanghai). 2017 Aug 1;49(8):655-668
pubmed: 28541389
J Clin Oncol. 2011 Oct 20;29(30):3999-4006
pubmed: 21931021
Cancers (Basel). 2017 Sep 27;9(10):
pubmed: 28953239
Mol Cancer Ther. 2018 Dec;17(12):2551-2563
pubmed: 30217967
Genome Biol. 2015 Dec 16;16:281
pubmed: 26673418
CNS Drugs. 2020 Nov;34(11):1121-1131
pubmed: 32965590
Nat Genet. 2014 May;46(5):451-6
pubmed: 24705254
Genome Biol. 2014;15(12):554
pubmed: 25476604
Nat Protoc. 2019 Mar;14(3):756-780
pubmed: 30710114
Comput Struct Biotechnol J. 2015 Sep 25;13:504-13
pubmed: 26949479
Br J Cancer. 2007 Dec 17;97(12):1664-72
pubmed: 18026198
BMC Cancer. 2016 Aug 18;16:647
pubmed: 27538997
Mutat Res. 2020 May - Dec;821:111716
pubmed: 32738522
Cancer Sci. 2013 Sep;104(9):1205-10
pubmed: 23745793
J Neurosurg Pediatr. 2010 Jul;6(1):98-105
pubmed: 20593995
J Clin Oncol. 2010 Jun 20;28(18):3061-8
pubmed: 20479398
Int J Radiat Oncol Biol Phys. 2010 May 1;77(1):253-60
pubmed: 20394857
EBioMedicine. 2019 Dec;50:81-92
pubmed: 31735550
Oncotarget. 2017 Apr 4;8(14):23937-23954
pubmed: 28147341
ChemMedChem. 2016 Jun 6;11(11):1117-21
pubmed: 27218427
J Neurooncol. 2012 May;107(3):517-26
pubmed: 22246202
Science. 2014 Jan 3;343(6166):80-4
pubmed: 24336569
Clin Cancer Res. 2018 May 1;24(9):2159-2170
pubmed: 29463553
Clin Cancer Res. 2018 Nov 15;24(22):5645-5657
pubmed: 30061363
Brain Pathol. 2013 May;23(3):244-53
pubmed: 22971244
Oncotarget. 2018 Jan 08;9(12):10497-10509
pubmed: 29535822
Genes Cells. 2002 Nov;7(11):1173-82
pubmed: 12390251
J Clin Oncol. 2019 Mar 10;37(8):613-623
pubmed: 30707661
Mol Cell. 2012 Feb 10;45(3):371-83
pubmed: 22325354
Cell Cycle. 2014;13(14):2237-47
pubmed: 24874015
Neuro Oncol. 2011 Dec;13(12):1296-307
pubmed: 21946044
Sci Rep. 2015 Oct 27;5:15666
pubmed: 26503893
Cancer Cell. 2006 Apr;9(4):287-300
pubmed: 16616334
Nat Rev Cancer. 2010 Dec;10(12):825-41
pubmed: 21102634
Neuro Oncol. 2017 Feb 1;19(2):153-161
pubmed: 27282398
Eur J Cancer. 2013 Sep;49(14):3020-8
pubmed: 23790466