Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma.
STAT3
STAT5
T-cell
lymphoma
targeting
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 12 2022
07 12 2022
Historique:
revised:
26
09
2022
received:
28
09
2021
accepted:
02
10
2022
pubmed:
8
11
2022
medline:
15
12
2022
entrez:
7
11
2022
Statut:
ppublish
Résumé
Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL.
Identifiants
pubmed: 36341492
doi: 10.15252/emmm.202115200
pmc: PMC9727928
doi:
Substances chimiques
p21-Activated Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e15200Subventions
Organisme : Austrian Science Fund FWF
ID : I 4157
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : I 4218
Pays : Austria
Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
Références
J Invest Dermatol. 2018 May;138(5):1116-1125
pubmed: 29128259
Blood. 2019 Aug 1;134(5):445-455
pubmed: 31167801
EMBO Mol Med. 2022 Dec 7;14(12):e15200
pubmed: 36341492
J Invest Dermatol. 2012 Jan;132(1):188-97
pubmed: 21881587
Leukemia. 2001 May;15(5):787-93
pubmed: 11368440
Cytogenet Genome Res. 2007;118(2-4):353-61
pubmed: 18000390
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
F1000Res. 2016 Jul 28;5:
pubmed: 27540476
J Dermatol Sci. 2018 Apr;90(1):60-67
pubmed: 29307600
Blood. 1996 Oct 1;88(7):2385-409
pubmed: 8839829
Acta Derm Venereol. 2019 Oct 1;99(11):1022-1028
pubmed: 31304555
J Biol Chem. 2013 Oct 4;288(40):29105-14
pubmed: 23960073
Cancer Cell. 2019 Jan 14;35(1):125-139.e9
pubmed: 30645971
J Invest Dermatol. 2010 Apr;130(4):1126-35
pubmed: 19759554
J Biochem Mol Toxicol. 2008 Nov-Dec;22(6):396-404
pubmed: 19111001
Am J Pathol. 2013 Jun;182(6):2264-75
pubmed: 23660011
Blood Adv. 2019 Feb 26;3(4):519-530
pubmed: 30770361
Bioorg Med Chem. 2010 Mar 1;18(5):1948-57
pubmed: 20171108
Blood. 2009 Jan 1;113(1):127-36
pubmed: 18832135
Cancers (Basel). 2019 Dec 03;11(12):
pubmed: 31817042
Cell Cycle. 2014;13(21):3331-5
pubmed: 25485578
Blood. 2016 Jun 30;127(26):3387-97
pubmed: 27121473
Nat Commun. 2017 Nov 6;8(1):1324
pubmed: 29109393
Blood. 2017 Sep 21;130(12):1430-1440
pubmed: 28694326
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Front Immunol. 2021 Aug 05;12:680334
pubmed: 34421895
Nat Genet. 2015 Dec;47(12):1465-70
pubmed: 26551667
Mol Cancer Ther. 2013 Dec;12(12):2651-62
pubmed: 24130053
Comput Struct Biotechnol J. 2015 Sep 25;13:504-13
pubmed: 26949479
J Exp Clin Cancer Res. 2010 Feb 11;29:11
pubmed: 20149229
Am J Clin Dermatol. 2016 Jun;17(3):225-37
pubmed: 26923912
Blood. 2019 Apr 18;133(16):1703-1714
pubmed: 30635287
J Clin Oncol. 2010 Nov 1;28(31):4730-9
pubmed: 20855822
Cancer Res. 2009 Nov 1;69(21):8438-46
pubmed: 19843862
Nat Genet. 2015 Dec;47(12):1426-34
pubmed: 26551670
Blood. 2004 Jul 15;104(2):328-35
pubmed: 15044256
Nat Rev Cancer. 2020 Sep;20(9):516-531
pubmed: 32632251
Nat Genet. 2015 Sep;47(9):1011-9
pubmed: 26192916
Blood. 2005 May 15;105(10):3768-85
pubmed: 15692063
J Invest Dermatol. 2016 Jul;136(7):1490-1499
pubmed: 27039262
J Invest Dermatol. 2010 Jun;130(6):1707-18
pubmed: 20130593
Chem Biol Interact. 2008 Oct 22;176(1):40-7
pubmed: 18638462
Genome Med. 2018 Apr 25;10(1):33
pubmed: 29695279
Cell Death Dis. 2018 Dec 5;9(12):1178
pubmed: 30518749
Acta Pharm Sin B. 2020 Apr;10(4):603-614
pubmed: 32322465
Genes Chromosomes Cancer. 2018 Dec;57(12):653-664
pubmed: 30144205
Leukemia. 2014 Mar;28(3):629-41
pubmed: 24263804
Br J Dermatol. 2014 Jun;170(6):1226-36
pubmed: 24641480
Cell Rep. 2014 Nov 20;9(4):1333-48
pubmed: 25456130
Nucleic Acids Res. 2020 Jul 2;48(W1):W488-W493
pubmed: 32246720
Immunity. 2012 Apr 20;36(4):542-50
pubmed: 22520847
Cancer Res. 2008 May 15;68(10):3785-94
pubmed: 18483262
PLoS One. 2013;8(1):e53767
pubmed: 23372669
Blood. 2015 Jul 23;126(4):508-19
pubmed: 26082451
Blood. 1998 Jan 15;91(2):570-6
pubmed: 9427711
Exp Dermatol. 2004 Jul;13(7):406-12
pubmed: 15217360
Nat Commun. 2015 Sep 29;6:8470
pubmed: 26415585
Blood. 2007 Oct 15;110(8):3015-27
pubmed: 17638852
Front Cell Dev Biol. 2021 Mar 16;9:641381
pubmed: 33796531
Leukemia. 2018 May;32(5):1135-1146
pubmed: 29472718
Blood. 2016 Aug 11;128(6):805-15
pubmed: 27268084