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Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL
T. Erdmann, P. Klener, JT. Lynch, M. Grau, P. Vočková, J. Molinsky, D. Tuskova, K. Hudson, UM. Polanska, M. Grondine, M. Mayo, B. Dai, M. Pfeifer, K. Erdmann, D. Schwammbach, M. Zapukhlyak, AM. Staiger, G. Ott, WE. Berdel, BR. Davies, F....
Language English Country United States
Document type Journal Article
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NV15-27757A
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- MeSH
- Apoptosis drug effects MeSH
- Lymphoma, Large B-Cell, Diffuse classification drug therapy genetics pathology MeSH
- Drug Combinations MeSH
- Phosphatidylinositol 3-Kinases genetics metabolism MeSH
- PTEN Phosphohydrolase deficiency genetics MeSH
- Phosphoinositide-3 Kinase Inhibitors MeSH
- Protein Kinase Inhibitors pharmacology MeSH
- Humans MeSH
- Mice MeSH
- NF-kappa B antagonists & inhibitors genetics metabolism MeSH
- Organ Specificity MeSH
- Oxadiazoles pharmacology MeSH
- Piperidines pharmacology MeSH
- Antineoplastic Agents pharmacology MeSH
- Proto-Oncogene Proteins c-akt antagonists & inhibitors genetics metabolism MeSH
- Proto-Oncogene Proteins c-myc antagonists & inhibitors genetics metabolism MeSH
- Pyrazoles pharmacology MeSH
- Pyrimidines pharmacology MeSH
- Pyrroles pharmacology MeSH
- Gene Expression Regulation, Neoplastic * MeSH
- Drug Screening Assays, Antitumor MeSH
- Signal Transduction MeSH
- Drug Synergism MeSH
- Protein-Tyrosine Kinases antagonists & inhibitors genetics metabolism 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 (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.
Department of Clinical Pathology Robert Bosch Hospital Stuttgart Germany
Department of Physics Philipps University Marburg Germany
Division of Cancer Department of Surgery and Cancer Imperial College London United Kingdom
References provided by Crossref.org
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