Optimized induction of mitochondrial apoptosis for chemotherapy-free treatment of BCR-ABL+acute lymphoblastic leukemia.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Apoptosis
/ drug effects
Bridged Bicyclo Compounds, Heterocyclic
/ administration & dosage
Dasatinib
/ administration & dosage
Dexamethasone
/ administration & dosage
Drug Resistance, Neoplasm
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
/ drug therapy
Mice
Mice, Inbred NOD
Mice, SCID
Mitochondria
/ drug effects
Sulfonamides
/ administration & dosage
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
25
07
2018
accepted:
07
11
2018
revised:
06
11
2018
pubmed:
14
12
2018
medline:
7
9
2019
entrez:
15
12
2018
Statut:
ppublish
Résumé
BCR-ABL+acute lymphoblastic leukemia (ALL) in adults has a poor prognosis with allogeneic stem cell transplantation (SCT) considered the best curative option for suitable patients. We here characterize the curative potential of BH3-mimetics differentially targeting mitochondrial BCL2-family members using a combination therapy approach with dexamethasone and tyrosine kinase inhibitors targeting BCR-ABL. In BCR-ABL + ALL BH3-mimetics act by redistribution of mitochondrial activator BIM, which is strongly required for cytotoxicity of the BCL2-specific BH3-mimetic ABT-199, tyrosine kinase inhibitors (TKIs) and dexamethasone. BIM expression is enhanced by dexamethasone and TKIs and both synergize with ABT-199 in BCR-ABL + ALL. Triple combinations with ABT-199, dexamethasone and TKIs efficiently attenuate leukemia progression both in tissue culture and in primary cell xenotransplantation models. Notably, the dasatinib-containing combination led to treatment- and leukemia-free long-term survival in a BCR-ABL + mouse model. Finally, response to BH3-mimetics can be predicted for individual patients in a clinically relevant setting. These data demonstrate curative targeted and chemotherapy-free pharmacotherapy for BCR-ABL + ALL in a preclinical model. Clinical evaluation, in particular for patients not suitable for allogeneic SCT, is warranted.
Identifiants
pubmed: 30546081
doi: 10.1038/s41375-018-0315-6
pii: 10.1038/s41375-018-0315-6
pmc: PMC6756054
doi:
Substances chimiques
Bridged Bicyclo Compounds, Heterocyclic
0
Sulfonamides
0
Dexamethasone
7S5I7G3JQL
venetoclax
N54AIC43PW
Dasatinib
RBZ1571X5H
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1313-1323Références
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