Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation.
cardiotoxicity
heart failure
inflammation
paquinimod
ponatinib
Journal
Circulation research
ISSN: 1524-4571
Titre abrégé: Circ Res
Pays: United States
ID NLM: 0047103
Informations de publication
Date de publication:
03 02 2023
03 02 2023
Historique:
pmc-release:
03
02
2024
pubmed:
11
1
2023
medline:
7
2
2023
entrez:
10
1
2023
Statut:
ppublish
Résumé
The tyrosine kinase inhibitor ponatinib is the only treatment option for chronic myelogenous leukemia patients with T315I (gatekeeper) mutation. Pharmacovigilance analysis of Food and Drug Administration and World Health Organization datasets has revealed that ponatinib is the most cardiotoxic agent among all Food and Drug Administration-approved tyrosine kinase inhibitors in a real-world scenario. However, the mechanism of ponatinib-induced cardiotoxicity is unknown. The lack of well-optimized mouse models has hampered the in vivo cardio-oncology studies. Here, we show that cardiovascular comorbidity mouse models evidence a robust cardiac pathological phenotype upon ponatinib treatment. A combination of multiple in vitro and in vivo models was employed to delineate the underlying molecular mechanisms. An unbiased RNA sequencing analysis identified the enrichment of dysregulated inflammatory genes, including a multifold upregulation of alarmins S100A8/A9, as a top hit in ponatinib-treated hearts. Mechanistically, we demonstrate that ponatinib activates the S100A8/A9-TLR4 (Toll-like receptor 4)-NLRP3 (NLR family pyrin domain-containing 3)-IL (interleukin)-1β signaling pathway in cardiac and systemic myeloid cells, in vitro and in vivo, thereby leading to excessive myocardial and systemic inflammation. Excessive inflammation was central to the cardiac pathology because interventions with broad-spectrum immunosuppressive glucocorticoid dexamethasone or specific inhibitors of NLRP3 (CY-09) or S100A9 (paquinimod) nearly abolished the ponatinib-induced cardiac dysfunction. Taken together, these findings uncover a novel mechanism of ponatinib-induced cardiac inflammation leading to cardiac dysfunction. From a translational perspective, our results provide critical preclinical data and rationale for a clinical investigation into immunosuppressive interventions for managing ponatinib-induced cardiotoxicity.
Sections du résumé
BACKGROUND
The tyrosine kinase inhibitor ponatinib is the only treatment option for chronic myelogenous leukemia patients with T315I (gatekeeper) mutation. Pharmacovigilance analysis of Food and Drug Administration and World Health Organization datasets has revealed that ponatinib is the most cardiotoxic agent among all Food and Drug Administration-approved tyrosine kinase inhibitors in a real-world scenario. However, the mechanism of ponatinib-induced cardiotoxicity is unknown.
METHODS
The lack of well-optimized mouse models has hampered the in vivo cardio-oncology studies. Here, we show that cardiovascular comorbidity mouse models evidence a robust cardiac pathological phenotype upon ponatinib treatment. A combination of multiple in vitro and in vivo models was employed to delineate the underlying molecular mechanisms.
RESULTS
An unbiased RNA sequencing analysis identified the enrichment of dysregulated inflammatory genes, including a multifold upregulation of alarmins S100A8/A9, as a top hit in ponatinib-treated hearts. Mechanistically, we demonstrate that ponatinib activates the S100A8/A9-TLR4 (Toll-like receptor 4)-NLRP3 (NLR family pyrin domain-containing 3)-IL (interleukin)-1β signaling pathway in cardiac and systemic myeloid cells, in vitro and in vivo, thereby leading to excessive myocardial and systemic inflammation. Excessive inflammation was central to the cardiac pathology because interventions with broad-spectrum immunosuppressive glucocorticoid dexamethasone or specific inhibitors of NLRP3 (CY-09) or S100A9 (paquinimod) nearly abolished the ponatinib-induced cardiac dysfunction.
CONCLUSIONS
Taken together, these findings uncover a novel mechanism of ponatinib-induced cardiac inflammation leading to cardiac dysfunction. From a translational perspective, our results provide critical preclinical data and rationale for a clinical investigation into immunosuppressive interventions for managing ponatinib-induced cardiotoxicity.
Identifiants
pubmed: 36625265
doi: 10.1161/CIRCRESAHA.122.321504
pmc: PMC9898181
mid: NIHMS1861661
doi:
Substances chimiques
ponatinib
4340891KFS
NLR Family, Pyrin Domain-Containing 3 Protein
0
Calgranulin A
0
Nlrp3 protein, mouse
0
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
267-289Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL147549
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL157999
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL125735
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133290
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL143074
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL119234
Pays : United States
Références
Circulation. 2020 Mar 31;141(13):1080-1094
pubmed: 31941367
Front Immunol. 2018 May 16;9:1075
pubmed: 29868027
Eur J Immunol. 2011 May;41(5):1203-17
pubmed: 21523780
Circulation. 2012 Jan 3;125(1):65-75
pubmed: 22086876
Cardiovasc Res. 2019 Apr 15;115(5):966-977
pubmed: 30629146
Circulation. 2014 May 27;129(21):2111-24
pubmed: 24657994
Arthritis Rheum. 2012 May;64(5):1579-88
pubmed: 22131101
Front Oncol. 2021 Mar 16;11:642005
pubmed: 33796468
Circulation. 2005 Sep 6;112(10):1428-34
pubmed: 16129801
J Am Heart Assoc. 2020 Sep 15;9(18):e018403
pubmed: 32893704
J Clin Oncol. 2015 Dec 10;33(35):4210-8
pubmed: 26371140
Clin Med (Lond). 2020 Mar;20(2):163-168
pubmed: 32188652
Cancer Cell. 2009 Nov 6;16(5):401-12
pubmed: 19878872
Circ Heart Fail. 2017 Mar;10(3):e003688
pubmed: 28242779
Basic Res Cardiol. 2013 Jul;108(4):356
pubmed: 23740214
Front Oncol. 2019 Jul 03;9:603
pubmed: 31334123
Int J Mol Sci. 2021 May 28;22(11):
pubmed: 34071707
Circulation. 2014 Jul 29;130(5):419-30
pubmed: 24899689
Eur J Heart Fail. 2017 Nov;19(11):1379-1389
pubmed: 28891154
Acta Haematol. 2020;143(3):217-231
pubmed: 31590170
JACC Basic Transl Sci. 2016 Aug;1(5):386-398
pubmed: 28713868
Arthritis Res Ther. 2021 Jul 31;23(1):204
pubmed: 34330322
Heart Fail Rev. 2013 Nov;18(6):835-45
pubmed: 23054221
Nat Rev Immunol. 2018 Dec;18(12):733-744
pubmed: 30228378
Nat Med. 2016 Jan;22(1):64-71
pubmed: 26692332
Am J Pathol. 2008 Jan;172(1):146-55
pubmed: 18156204
Circ Res. 2015 Mar 27;116(7):1254-68
pubmed: 25814686
J Clin Oncol. 2018 Jun 10;36(17):1714-1768
pubmed: 29442540
Lancet Haematol. 2018 Dec;5(12):e618-e627
pubmed: 30501869
Clin Chim Acta. 2015 Mar 30;443:71-7
pubmed: 25199849
J Exp Med. 2012 Jan 16;209(1):123-37
pubmed: 22213805
Front Immunol. 2019 Jun 21;10:1393
pubmed: 31293574
Oncologist. 2015 Aug;20(8):847-8
pubmed: 26173838
J Med Case Rep. 2021 Mar 25;15(1):164
pubmed: 33762010
Nat Rev Cardiol. 2020 May;17(5):269-285
pubmed: 31969688
Eur Heart J. 2019 Jun 7;40(22):1771-1777
pubmed: 29982507
Mediators Inflamm. 2013;2013:828354
pubmed: 24453429
J Immunol. 2003 Mar 15;170(6):3233-42
pubmed: 12626582
Cancer Cell. 2019 Oct 14;36(4):431-443.e5
pubmed: 31543464
Nat Commun. 2020 Sep 23;11(1):4809
pubmed: 32968055
J Am Coll Cardiol. 2016 Mar 8;67(9):1091-1103
pubmed: 26940931
Sci Transl Med. 2017 Feb 15;9(377):
pubmed: 28202772
Circulation. 2019 Mar 26;139(13):e579-e602
pubmed: 30786722
Nat Med. 2007 Feb;13(2):139-45
pubmed: 17290272
J Clin Oncol. 2009 Sep 10;27(26):4398-405
pubmed: 19636013
Nat Rev Immunol. 2021 Jun;21(6):363-381
pubmed: 33340021
Leuk Res. 2016 Sep;48:84-91
pubmed: 27505637
Curr Treat Options Cardiovasc Med. 2018 Jun 19;20(7):53
pubmed: 29922881
Curr Cancer Drug Targets. 2018;18(9):847-856
pubmed: 28969556
Circ Res. 2016 Apr 15;118(8):1208-22
pubmed: 26976650
Heart Fail Rev. 2020 May;25(3):447-456
pubmed: 32026180
JCI Insight. 2016 Jun 16;1(9):
pubmed: 27366791
Br J Pharmacol. 2015 Feb;172(4):957-74
pubmed: 25302413
Curr Treat Options Cardiovasc Med. 2017 Apr;19(4):24
pubmed: 28316033
Am J Physiol Heart Circ Physiol. 2019 Jul 1;317(1):H124-H140
pubmed: 31074651
Int J Oncol. 2019 Jul;55(1):289-297
pubmed: 31115499
J Card Fail. 2008 Feb;14(1):61-74
pubmed: 18226775
Nature. 2020 Dec;588(7838):466-472
pubmed: 32971526
Leukemia. 2013 Jan;27(1):32-40
pubmed: 22781593
Circulation. 2003 Jul 1;107(25):3133-40
pubmed: 12796126
Leukemia. 2006 Mar;20(3):400-3
pubmed: 16437142
JAMA Oncol. 2016 May 01;2(5):625-632
pubmed: 26847662
Virol J. 2011 Jun 02;8:267
pubmed: 21635745
Am J Transl Res. 2017 Mar 15;9(3):1335-1343
pubmed: 28386359
Toxicol Sci. 2015 Jan;143(1):147-55
pubmed: 25304212
Drugs. 2014 May;74(7):793-806
pubmed: 24807266
Circ Res. 2014 Jan 17;114(2):266-82
pubmed: 24186967
Circ Res. 2016 Jun 24;119(1):159-76
pubmed: 27340274
J Exp Med. 2017 Nov 6;214(11):3219-3238
pubmed: 29021150
JAMA. 2014 Jan 22-29;311(4):353-4
pubmed: 24449310
PLoS One. 2013 Aug 19;8(8):e72138
pubmed: 23977231
Front Immunol. 2018 Jun 11;9:1298
pubmed: 29942307
Pharmacol Res. 2020 Nov;161:105212
pubmed: 32991974
Ann Rheum Dis. 2015 Dec;74(12):2254-8
pubmed: 25969431
J Mol Cell Cardiol. 2019 May;130:65-75
pubmed: 30928428
Science. 2009 Jul 31;325(5940):612-6
pubmed: 19644120
Cardiooncology. 2016 Nov 15;2(1):9
pubmed: 33530146
J Clin Invest. 2010 Jul;120(7):2280-91
pubmed: 20516643
N Engl J Med. 2001 Apr 5;344(14):1031-7
pubmed: 11287972
Hum Pathol. 2017 Apr;62:83-90
pubmed: 28025077
Mol Cancer Ther. 2012 Mar;11(3):690-9
pubmed: 22238366
J Clin Oncol. 2011 Jan 10;29(2):174-85
pubmed: 21135271
JACC Basic Transl Sci. 2019 Jan 16;4(1):41-53
pubmed: 30847418
Chemotherapy. 2019;64(4):205-209
pubmed: 31825920
Ther Adv Hematol. 2019 Mar 01;10:2040620719826444
pubmed: 30854182