Copanlisib synergizes with conventional and targeted agents including venetoclax in B- and T-cell lymphoma models.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
10 03 2020
10 03 2020
Historique:
received:
14
08
2019
accepted:
31
01
2020
entrez:
4
3
2020
pubmed:
4
3
2020
medline:
15
5
2021
Statut:
ppublish
Résumé
Copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor with preferred activity toward PI3Kα and PI3Kδ. Despite the clear overall clinical benefit, the number of patients achieving complete remissions with the single agent is relatively low, a problem shared by the vast majority of targeted agents. Here, we searched for novel copanlisib-based combinations. Copanlisib was tested as a single agent, in combination with an additional 17 drugs in 26 cell lines derived from mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and T-cell lymphomas. In vivo experiments, transcriptome analyses, and immunoblotting experiments were also performed. Copanlisib as a single agent showed in vitro dose-dependent antitumor activity in the vast majority of the models. Combination screening identified several compounds that synergized with copanlisib. The strongest combination was with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. The benefit of the combination over single agents was also validated in an MZL xenograft model and in MCL primary cells, and was due to increased induction of apoptosis, an effect likely sustained by the reduction of the antiapoptotic proteins myeloid cell leukemia 1 (MCL1) and BCL-XL, observed in MCL and MZL cell lines, respectively. These data supported the rationale for the design of the Swiss Group for Clinical Cancer Research (SAKK) 66/18 phase 1 study currently exploring the combination of copanlisib and venetoclax in relapsed/refractory lymphomas.
Identifiants
pubmed: 32126142
pii: S2473-9529(20)31446-4
doi: 10.1182/bloodadvances.2019000844
pmc: PMC7065481
doi:
Substances chimiques
Bridged Bicyclo Compounds, Heterocyclic
0
Pyrimidines
0
Quinazolines
0
Sulfonamides
0
venetoclax
N54AIC43PW
copanlisib
WI6V529FZ9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
819-829Informations de copyright
© 2020 by The American Society of Hematology.
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