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First-in-class inhibitor of HSP110 blocks BCR activation through SYK phosphorylation in diffuse large B-cell lymphoma
VC. Gibouin, M. Durand, C. Boudesco, F. Hermetet, K. Nozickova, C. Chassagne-Clement, M. Abdelwahed, P. Klener, C. Garrido, G. Jego
Language English Country England, Great Britain
Document type Journal Article
Grant support
EL2023 LNCC/CaG
Ligue Contre le Cancer
ANR-11-LABX-0021
Agence Nationale de la Recherche (French National Research Agency)
ANR-11-LABX-0051
Agence Nationale de la Recherche (French National Research Agency)
ANR-15-IDE-0003
Agence Nationale de la Recherche (French National Research Agency)
NLK
ProQuest Central
from 2000-01-01 to 1 year ago
Open Access Digital Library
from 1997-01-01
Nursing & Allied Health Database (ProQuest)
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Public Health Database (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- Quinazolines MeSH
- Lymphoma, Large B-Cell, Diffuse * drug therapy metabolism pathology MeSH
- Phosphorylation drug effects MeSH
- Syk Kinase * antagonists & inhibitors metabolism MeSH
- Humans MeSH
- Mice, SCID MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Tumor Cells, Cultured MeSH
- HSP110 Heat-Shock Proteins * metabolism MeSH
- Pyrimidines pharmacology MeSH
- Receptors, Antigen, B-Cell * metabolism MeSH
- Signal Transduction * drug effects MeSH
- Xenograft Model Antitumor Assays * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is driven by aberrant activation of the B-cell receptor (BCR) and the TLR/MyD88 signaling pathways. The heat-shock protein HSP110 is a candidate for their regulation as it stabilizes MyD88. However, its role in overall BCR signaling remains unknown. Here, we used first-in-class HSP110 inhibitors to address this question. HSP110 inhibitors decreased the survival of several ABC-DLBCL cell lines in vitro and in vivo, and reduced the phosphorylation of BCR signaling kinases, including BTK and SYK. We identified an interaction between HSP110 and SYK and demonstrated that HSP110 promotes SYK phosphorylation. Finally, the combination of the HSP110 inhibitor with the PI3K inhibitor copanlisib decreases SYK/BTK and AKT phosphorylation synergistically, leading to suppression of tumor growth in cell line xenografts and strong reduction in patient-derived xenografts. In conclusion, by regulating the BCR/TLR signaling pathway, HSP110 inhibitors are potential drug candidates for ABC-DLBCL patients.
Centre Georges François Leclerc 21000 Dijon France
Equipe Labellisée « Ligue Nationale Contre le Cancer » Paris France
References provided by Crossref.org
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- $a Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is driven by aberrant activation of the B-cell receptor (BCR) and the TLR/MyD88 signaling pathways. The heat-shock protein HSP110 is a candidate for their regulation as it stabilizes MyD88. However, its role in overall BCR signaling remains unknown. Here, we used first-in-class HSP110 inhibitors to address this question. HSP110 inhibitors decreased the survival of several ABC-DLBCL cell lines in vitro and in vivo, and reduced the phosphorylation of BCR signaling kinases, including BTK and SYK. We identified an interaction between HSP110 and SYK and demonstrated that HSP110 promotes SYK phosphorylation. Finally, the combination of the HSP110 inhibitor with the PI3K inhibitor copanlisib decreases SYK/BTK and AKT phosphorylation synergistically, leading to suppression of tumor growth in cell line xenografts and strong reduction in patient-derived xenografts. In conclusion, by regulating the BCR/TLR signaling pathway, HSP110 inhibitors are potential drug candidates for ABC-DLBCL patients.
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