The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.
- MeSH
- apoptóza účinky léků MeSH
- bicyklické sloučeniny heterocyklické * farmakologie terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom * farmakoterapie patologie MeSH
- fosfohydroláza PTEN metabolismus MeSH
- lidé MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protokoly protinádorové kombinované chemoterapie * farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- protoonkogenní proteiny c-bcl-2 * antagonisté a inhibitory metabolismus MeSH
- pyrimidiny * farmakologie terapeutické užití MeSH
- pyrroly farmakologie terapeutické užití MeSH
- rituximab farmakologie terapeutické užití MeSH
- sulfonamidy * farmakologie terapeutické užití MeSH
- xenogenní modely - testy protinádorové aktivity * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- BCL2 protein, human MeSH Prohlížeč
- bicyklické sloučeniny heterocyklické * MeSH
- capivasertib MeSH Prohlížeč
- fosfohydroláza PTEN MeSH
- protoonkogenní proteiny c-akt * MeSH
- protoonkogenní proteiny c-bcl-2 * MeSH
- pyrimidiny * MeSH
- pyrroly MeSH
- rituximab MeSH
- sulfonamidy * MeSH
- venetoclax MeSH Prohlížeč
