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.
- MeSH
- adenin analogy a deriváty MeSH
- apoptóza účinky léků MeSH
- difúzní velkobuněčný B-lymfom klasifikace farmakoterapie genetika patologie MeSH
- fixní kombinace léků MeSH
- fosfatidylinositol-3-kinasy genetika metabolismus MeSH
- fosfohydroláza PTEN nedostatek genetika MeSH
- inhibitory fosfoinositid-3-kinasy MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- myši MeSH
- NF-kappa B antagonisté a inhibitory genetika metabolismus MeSH
- orgánová specificita MeSH
- oxadiazoly farmakologie MeSH
- piperidiny farmakologie MeSH
- proteinkinasa BTK MeSH
- protinádorové látky farmakologie MeSH
- protoonkogenní proteiny c-akt antagonisté a inhibitory genetika metabolismus MeSH
- protoonkogenní proteiny c-myc antagonisté a inhibitory genetika metabolismus MeSH
- pyrazoly farmakologie MeSH
- pyrimidiny farmakologie MeSH
- pyrroly farmakologie MeSH
- regulace genové exprese u nádorů * MeSH
- screeningové testy protinádorových léčiv MeSH
- signální transdukce MeSH
- synergismus léků MeSH
- tyrosinkinasy antagonisté a inhibitory genetika metabolismus MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adenin MeSH
- AZD8835 MeSH Prohlížeč
- Btk protein, mouse MeSH Prohlížeč
- capivasertib MeSH Prohlížeč
- fixní kombinace léků MeSH
- fosfohydroláza PTEN MeSH
- ibrutinib MeSH Prohlížeč
- inhibitory fosfoinositid-3-kinasy MeSH
- inhibitory proteinkinas MeSH
- MYC protein, human MeSH Prohlížeč
- NF-kappa B MeSH
- oxadiazoly MeSH
- piperidiny MeSH
- proteinkinasa BTK MeSH
- protinádorové látky MeSH
- protoonkogenní proteiny c-akt MeSH
- protoonkogenní proteiny c-myc MeSH
- PTEN protein, human MeSH Prohlížeč
- pyrazoly MeSH
- pyrimidiny MeSH
- pyrroly MeSH
- tyrosinkinasy MeSH
