Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure.
Crenolanib
FLT3 inhibitors
FLT3 mutation
Gilteritinib
Midostaurin
Quizartinib
Sorafenib
acute myeloid leukemia
mechanism of resistance
overcoming resistance
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
02 Sep 2022
02 Sep 2022
Historique:
received:
26
05
2022
revised:
27
08
2022
accepted:
29
08
2022
entrez:
9
9
2022
pubmed:
10
9
2022
medline:
10
9
2022
Statut:
epublish
Résumé
FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30-40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30-50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.
Identifiants
pubmed: 36077850
pii: cancers14174315
doi: 10.3390/cancers14174315
pmc: PMC9454516
pii:
doi:
Types de publication
Journal Article
Review
Langues
eng
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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