Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL
| Autor: | Diana Tuskova, James T. Lynch, German Ott, Kevin Hudson, Wolfgang E. Berdel, Myroslav Zapukhlyak, Barry R. Davies, Simon T. Barry, Matthias Pfeifer, Jan Molinsky, Peter Lenz, Michele Mayo, Kristian Erdmann, Michael Grau, Petra Vockova, Pavel Klener, Marek Trneny, Annette M. Staiger, Daniela Schwammbach, Beiying Dai, Tabea Erdmann, Francisco Cruzalegui, Georg Lenz, Urszula M. Polanska, Michael Grondine |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Apoptosis Pharmacology Biochemistry Tyrosine-kinase inhibitor chemistry.chemical_compound Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Piperidines hemic and lymphatic diseases Agammaglobulinaemia Tyrosine Kinase Phosphoinositide-3 Kinase Inhibitors Oxadiazoles biology NF-kappa B Drug Synergism Hematology Protein-Tyrosine Kinases Gene Expression Regulation Neoplastic Drug Combinations Organ Specificity 030220 oncology & carcinogenesis Ibrutinib Lymphoma Large B-Cell Diffuse Signal transduction Signal Transduction medicine.drug_class Immunology Antineoplastic Agents Proto-Oncogene Proteins c-myc 03 medical and health sciences medicine Animals Humans Pyrroles Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Phosphoinositide 3-kinase Akt inhibitor AZD5363 Adenine PTEN Phosphohydrolase Germinal center Cell Biology Xenograft Model Antitumor Assays 030104 developmental biology Pyrimidines chemistry biology.protein Cancer research Pyrazoles Drug Screening Assays Antitumor Proto-Oncogene Proteins c-akt |
| Zdroj: | Blood. 130(3) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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