Combination of a mitogen-activated protein kinase inhibitor with the tyrosine kinase inhibitor pacritinib combats cell adhesion-based residual disease and prevents re-expansion of FLT3-ITD acute myeloid leukaemia.
Adolescent
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Bridged-Ring Compounds
/ pharmacology
Cell Adhesion
/ drug effects
Child
Child, Preschool
Extracellular Signal-Regulated MAP Kinases
Female
Humans
Infant
Infant, Newborn
Leukemia, Myeloid, Acute
/ drug therapy
Male
Middle Aged
Models, Biological
Neoplasm, Residual
Protein Kinase Inhibitors
/ pharmacology
Pyrimidines
/ pharmacology
fms-Like Tyrosine Kinase 3
/ antagonists & inhibitors
acute myeloid leukaemia
drug resistance
microenvironment
minimal residual disease
tyrosine kinase inhibitors
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
24
02
2020
accepted:
23
03
2020
pubmed:
13
5
2020
medline:
17
3
2021
entrez:
13
5
2020
Statut:
ppublish
Résumé
Minimal residual disease (MRD) in acute myeloid leukaemia (AML) poses a major challenge due to drug insensitivity and high risk of relapse. Intensification of chemotherapy and stem cell transplantation are often pivoted on MRD status. Relapse rates are high even with the integration of first-generation FMS-like tyrosine kinase 3 (FLT3) inhibitors in pre- and post-transplant regimes and as maintenance in FLT3-mutated AML. Pre-clinical progress is hampered by the lack of suitable modelling of residual disease and post-therapy relapse. In the present study, we investigated the nature of pro-survival signalling in primary residual tyrosine kinase inhibitor (TKI)-treated AML cells adherent to stroma and further determined their drug sensitivity in order to inform rational future therapy combinations. Using a primary human leukaemia-human stroma model to mimic the cell-cell interactions occurring in patients, the ability of several TKIs in clinical use, to abrogate stroma-driven leukaemic signalling was determined, and a synergistic combination with a mitogen-activated protein kinase (MEK) inhibitor identified for potential therapeutic application in the MRD setting. The findings reveal a common mechanism of stroma-mediated resistance that may be independent of mutational status but can be targeted through rational drug design, to eradicate MRD and reduce treatment-related toxicity.
Substances chimiques
11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
0
Bridged-Ring Compounds
0
Protein Kinase Inhibitors
0
Pyrimidines
0
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
231-242Subventions
Organisme : HCRW_
ID : HCRW_HRG-16-1318
Pays : United Kingdom
Organisme : Experimental Cancer Medicine Centre
Organisme : Leukaemia Research Appeal for Wales
ID : CAAML/01/2016
Informations de copyright
© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
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