Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Blood, 2017-07, Vol.130 (3), p.310-322

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.