Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo.
Cell Line, Tumor
Drug Resistance, Neoplasm
/ genetics
Humans
Janus Kinases
/ genetics
Leukemia, Myeloid, Acute
/ drug therapy
Mutation
/ genetics
Protein Kinase Inhibitors
/ pharmacology
Sorafenib
/ pharmacology
Staurosporine
/ analogs & derivatives
Tandem Repeat Sequences
/ drug effects
fms-Like Tyrosine Kinase 3
/ antagonists & inhibitors
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
09
05
2020
accepted:
21
10
2020
revised:
13
10
2020
pubmed:
6
11
2020
medline:
17
8
2021
entrez:
5
11
2020
Statut:
ppublish
Résumé
An important limitation of FLT3 tyrosine kinase inhibitors (TKIs) in FLT3-ITD positive AML is the development of resistance. To better understand resistance to FLT3 inhibition, we examined FLT3-ITD positive cell lines which had acquired resistance to midostaurin or sorafenib. In 6 out of 23 TKI resistant cell lines we were able to detect a JAK1 V658F mutation, a mutation that led to reactivation of the CSF2RB-STAT5 pathway. Knockdown of JAK1, or treatment with a JAK inhibitor, resensitized cells to FLT3 inhibition. Out of 136 patients with FLT3-ITD mutated AML and exposed to FLT3 inhibitor, we found seven different JAK family mutations in six of the cases (4.4%), including five bona fide, activating mutations. Except for one patient, the JAK mutations occurred de novo (n = 4) or displayed increasing variant allele frequency after exposure to FLT3 TKI (n = 1). In vitro each of the five activating variants were found to induce resistance to FLT3-ITD inhibition, which was then overcome by dual FLT3/JAK inhibition. In conclusion, our data characterize a novel mechanism of resistance to FLT3-ITD inhibition and may offer a potential therapy, using dual JAK and FLT3 inhibition.
Identifiants
pubmed: 33149267
doi: 10.1038/s41375-020-01077-1
pii: 10.1038/s41375-020-01077-1
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Sorafenib
9ZOQ3TZI87
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Janus Kinases
EC 2.7.10.2
Staurosporine
H88EPA0A3N
midostaurin
ID912S5VON
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2017-2029Références
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