Autophagy and inflammasome activation are associated with poor response to FLT3 inhibitors in patients with FLT3-ITD acute myeloid leukemia.
fms-Like Tyrosine Kinase 3
/ genetics
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Autophagy
/ drug effects
Inflammasomes
/ metabolism
Protein Kinase Inhibitors
/ pharmacology
Mutation
Female
Male
Benzothiazoles
/ pharmacology
Middle Aged
Sorafenib
/ pharmacology
Drug Resistance, Neoplasm
/ genetics
Aged
Phenylurea Compounds
Drug resistance
Acute myeloid leukemia
Autophagy
FLT3-ITD inhibitors
Inflammasome
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
12 Oct 2024
12 Oct 2024
Historique:
received:
30
05
2024
accepted:
24
09
2024
medline:
13
10
2024
pubmed:
13
10
2024
entrez:
12
10
2024
Statut:
epublish
Résumé
Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.
Identifiants
pubmed: 39396074
doi: 10.1038/s41598-024-74168-z
pii: 10.1038/s41598-024-74168-z
doi:
Substances chimiques
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Inflammasomes
0
FLT3 protein, human
EC 2.7.10.1
Protein Kinase Inhibitors
0
quizartinib
7LA4O6Q0D3
Benzothiazoles
0
Sorafenib
9ZOQ3TZI87
Phenylurea Compounds
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
23882Subventions
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : #2022/03871-1
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : #2021/11112-0
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : #2013/08135-2
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
ID : 88887.650052/2021-00
Organisme : Conselho Nacional de Desenvolvimento Científico e Tecnológico
ID : 465539/2014-9
Informations de copyright
© 2024. The Author(s).
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