Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL

• Published in: Blood 2017-07, Vol.130 (3), p.310-322
• Main Authors: Erdmann, Tabea, Klener, Pavel, Lynch, James T., Grau, Michael, Vočková, Petra, Molinsky, Jan, Tuskova, Diana, Hudson, Kevin, Polanska, Urszula M., Grondine, Michael, Mayo, Michele, Dai, Beiying, Pfeifer, Matthias, Erdmann, Kristian, Schwammbach, Daniela, Zapukhlyak, Myroslav, Staiger, Annette M., Ott, German, Berdel, Wolfgang E., Davies, Barry R., Cruzalegui, Francisco, Trneny, Marek, Lenz, Peter, Barry, Simon T., Lenz, Georg
• Format: Article
• Language: English
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Drug Combinations; Drug Screening Assays, Antitumor; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Large B-Cell, Diffuse - classification; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Mice; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; Organ Specificity; Oxadiazoles - pharmacology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Piperidines - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - genetics; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Pyrroles - pharmacology; Signal Transduction; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-12-758599

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. •PI3Kα/δ inhibition induces cytotoxicity in ABC DLBCLs through downregulation of NF-κB signaling.•Inhibition of AKT induces cytotoxicity by downregulation of MYC in PTEN-deficient DLBCL models in vivo and in vitro.