Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319 in pre-clinical models of aggressive lymphomas.
Adenosine
/ administration & dosage
Agammaglobulinaemia Tyrosine Kinase
/ antagonists & inhibitors
Animals
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Benzamides
/ administration & dosage
Cell Proliferation
/ drug effects
Class I Phosphatidylinositol 3-Kinases
/ antagonists & inhibitors
Drug Synergism
Humans
Lymphoma, B-Cell
/ drug therapy
Lymphoma, B-Cell, Marginal Zone
/ drug therapy
Lymphoma, Large B-Cell, Diffuse
/ drug therapy
Lymphoma, Mantle-Cell
/ drug therapy
Mice, SCID
Protein Kinase Inhibitors
/ administration & dosage
Pyrazines
/ administration & dosage
Quinolines
/ administration & dosage
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
BTK
PI3K
acalabrutinib
ibrutinib
lymphomas
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
10
03
2019
accepted:
08
06
2019
pubmed:
30
7
2019
medline:
23
6
2020
entrez:
30
7
2019
Statut:
ppublish
Résumé
The B-cell receptor and the phosphatidylinositol 3-kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B-cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP-196) and ACP-319 (AMG-319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre-clinical models. The two compounds showed activity in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Two in vivo experiments with ABC DLBCL and MCL xenografts confirmed the effect of the single agents. Benefit was achieved by exposing the lymphoma cell lines to both acalabrutinib and ACP-319. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on-going current trials with acalabrutinib and ACP-319 as single agents and provide the basis for the investigation of their combination as well.
Substances chimiques
Benzamides
0
Protein Kinase Inhibitors
0
Pyrazines
0
Quinolines
0
N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine
19DG7G1U5Q
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CD protein, human
EC 2.7.1.137
Agammaglobulinaemia Tyrosine Kinase
EC 2.7.10.2
BTK protein, human
EC 2.7.10.2
acalabrutinib
I42748ELQW
Adenosine
K72T3FS567
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
595-601Informations de copyright
© 2019 British Society for Haematology and John Wiley & Sons Ltd.
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