Kinome multigenic panel identified novel druggable EPHB4-V871I somatic variant in high-risk neuroblastoma.
EPHB4
drug
high-risk neuroblastoma
kinases
personalized medicine
somatic mutation
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
03
09
2019
revised:
28
02
2020
accepted:
20
03
2020
pubmed:
27
4
2020
medline:
30
4
2021
entrez:
27
4
2020
Statut:
ppublish
Résumé
Neuroblastoma (NB) is the most common extracranial neoplasm in children. The overall outcome for high-risk NB patients is still unacceptable, therefore, it is critical to deeply understand molecular mechanisms associated with NB, which in turn can be utilized for developing drugs towards the treatment of NB. Protein kinases (TKs) play an essential role in the regulation of cell survival and proliferation. Different kinases, such as anaplastic lymphoma kinase (ALK), Aurora kinase, RET receptor tyrosine kinase, are potential therapeutic targets in various cancers, including NB. We analysed a cohort of 45 high-risk NB patients and 9 NB cell lines by a targeted-(t)NGS custom gene panel (genes codifying for the kinase domains of 90 TKs). We identified somatic variants in four TK genes (ALK, EPHB4, LMTK3 and EPHB6) in NB patients and we functionally characterized an interesting somatic variant, V871I, in EPHB4 gene. EPHB4 plays a crucial role in cardiovascular development and regulates vascularization in cancer-promoting angiogenesis, tumour growth and metastasis. Several EPHB4 mutations have previously been identified in solid and haematological tumour specimens but EPHB4 mutations were not described until now in NB. Interestingly, a re-analysis of public CGH-array showed that the EPHB4 gain is associated with advanced diseases in NB. We further demonstrated that higher EPHB4 expression is correlated to stage 4 of NB and with poor overall survival. Additionally, we also revealed that the EPHB4-V871I accounts for increased proliferation, migration and invasion properties in two NB cell lines by acting on VEGF, c-RAF and CDK4 target genes and by increasing the phosphorylation of ERK1-2 pathway. The use of two EPHB4 inhibitors, JI-101 and NVP-BHG712, was able to rescue the phenotype driven by the variant. Our study suggested that EPHB4 is a promising therapeutic target in high-risk NB.
Identifiants
pubmed: 32336043
doi: 10.1111/jcmm.15297
pmc: PMC7294133
doi:
Substances chimiques
EPHB4 protein, human
0
Protein Kinases
EC 2.7.-
Receptor, EphB4
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6459-6471Informations de copyright
© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
Références
Oncotarget. 2015 Nov 3;6(34):35247-62
pubmed: 26497213
Invest New Drugs. 2015 Dec;33(6):1217-24
pubmed: 26365907
Nat Genet. 2015 Dec;47(12):1411-4
pubmed: 26523776
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Neuro Oncol. 2012 May;14(5):596-612
pubmed: 22411914
Nat Rev Cancer. 2010 Mar;10(3):165-80
pubmed: 20179713
J Cell Mol Med. 2020 Jun;24(11):6459-6471
pubmed: 32336043
Cancer Cell. 2014 Nov 10;26(5):682-94
pubmed: 25517749
Thyroid. 2013 Feb;23(2):151-9
pubmed: 23398161
Expert Opin Orphan Drugs. 2017;5(4):355-368
pubmed: 29062613
EMBO Mol Med. 2010 May;2(5):146-58
pubmed: 20432502
Haematologica. 2016 Aug;101(8):909-17
pubmed: 27151991
Carcinogenesis. 2017 Oct 1;38(10):1011-1020
pubmed: 28968651
Cancer Res. 2017 Feb 15;77(4):971-981
pubmed: 27923830
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Nature. 2007 Mar 8;446(7132):153-8
pubmed: 17344846
J Natl Cancer Inst. 2006 Sep 6;98(17):1193-203
pubmed: 16954472
Semin Cell Dev Biol. 2012 Feb;23(1):51-7
pubmed: 22044885
Br J Cancer. 2012 Oct 9;107(8):1418-22
pubmed: 22976801
Curr Drug Targets. 2015;16(11):1233-45
pubmed: 25882221
EMBO Rep. 2018 May;19(5):
pubmed: 29643120
J Natl Cancer Inst. 2018 Oct 1;110(10):1084-1093
pubmed: 29514301
Clin Cancer Res. 2015 Jul 15;21(14):3327-39
pubmed: 25805801
Nat Rev Mol Cell Biol. 2016 Apr;17(4):240-56
pubmed: 26790531
Nat Genet. 2013 Mar;45(3):279-84
pubmed: 23334666
Oncotarget. 2016 Apr 19;7(16):21840-52
pubmed: 27009842
Cancer Discov. 2016 Jan;6(1):96-107
pubmed: 26554404
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Nat Genet. 2015 Aug;47(8):864-71
pubmed: 26121087
Cell. 1974 Dec;3(4):355-9
pubmed: 4442124
Curr Opin Cell Biol. 2008 Apr;20(2):194-200
pubmed: 18353626
Cell Physiol Biochem. 2017;41(2):819-834
pubmed: 28214829
Cell Cycle. 2012 Feb 1;11(3):569-81
pubmed: 22262177
Adv Cancer Res. 2012;114:1-20
pubmed: 22588054
Naunyn Schmiedebergs Arch Pharmacol. 2011 Oct;384(4-5):489-98
pubmed: 21553004
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
Nat Genet. 2013 Oct;45(10):1113-20
pubmed: 24071849
Exp Ther Med. 2020 Mar;19(3):1997-2007
pubmed: 32104259
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Cell Death Dis. 2013 Apr 11;4:e586
pubmed: 23579273
Genome Res. 2012 Mar;22(3):568-76
pubmed: 22300766
Nature. 2015 Oct 29;526(7575):700-4
pubmed: 26466568
Science. 2018 Dec 7;362(6419):1165-1170
pubmed: 30523111
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
J Mol Diagn. 2011 Jan;13(1):74-84
pubmed: 21227397
Eur J Cancer. 2019 Apr;111:50-58
pubmed: 30822684
Cancer Treat Res. 2010;155:65-84
pubmed: 20517688
Angiogenesis. 2010 Sep;13(3):259-67
pubmed: 20803239
Semin Cancer Biol. 2019 Jun;56:37-46
pubmed: 28993206
J Transl Med. 2016 May 17;14(1):142
pubmed: 27188717
N Engl J Med. 2010 Jun 10;362(23):2202-11
pubmed: 20558371
Clin Cancer Res. 2012 May 1;18(9):2423-8
pubmed: 22427348
Sci Rep. 2015 Jun 15;5:10641
pubmed: 26073592