title: Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL.
abstract: 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.
authors.affiliation: Translational Oncology, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.|Fachbereich Chemie und Pharmazie, University of Münster, Münster, Germany.
authors.forename: Tabea
authors.initials: T
authors.lastname: Erdmann
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic.|First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
authors.affiliation: Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: James T
authors.initials: JT
authors.lastname: Lynch
authors.affiliation: Translational Oncology, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic.|First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Vočková
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic.|First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Molinsky
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic.|First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Diana
authors.initials: D
authors.lastname: Tuskova
authors.affiliation: Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hudson
authors.affiliation: Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Urszula M
authors.initials: UM
authors.lastname: Polanska
authors.affiliation: IMED Oncology AstraZeneca, Gatehouse Park, Boston, MA.
authors.forename: Michael
authors.initials: M
authors.lastname: Grondine
authors.affiliation: IMED Oncology AstraZeneca, Gatehouse Park, Boston, MA.
authors.forename: Michele
authors.initials: M
authors.lastname: Mayo
authors.affiliation: Translational Oncology, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Beiying
authors.initials: B
authors.lastname: Dai
authors.affiliation: Division of Cancer, Department of Surgery & Cancer, Imperial College, London, United Kingdom.
authors.forename: Matthias
authors.initials: M
authors.lastname: Pfeifer
authors.affiliation: Translational Oncology, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Erdmann
authors.affiliation: Translational Oncology, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schwammbach
authors.affiliation: Translational Oncology, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.
authors.forename: Myroslav
authors.initials: M
authors.lastname: Zapukhlyak
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Hospital, Stuttgart, Germany.|Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Staiger
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Hospital, Stuttgart, Germany.
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.affiliation: Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.|Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany; and.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.affiliation: Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruzalegui
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic.|First Medical Department, Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trneny
authors.affiliation: Department of Physics, Philipps University, Marburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.affiliation: Innovative Medicines and Early Development (IMED) Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
authors.affiliation: Translational Oncology, University Hospital Münster, Münster, Germany.|Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany.|Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany; and.
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D010069:Oxadiazoles / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000225:Adenine; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents; D004338:Drug Combinations; D016328:NF-kappa B; D010069:Oxadiazoles; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; C000609108:AZD8835; C489427:MYC protein, human; C551803:ibrutinib; C000625951:Btk protein, mouse; C494929:PTEN protein, human; C575618:capivasertib