Targeting Bfl-1 via acute CDK9 inhibition overcomes intrinsic BH3-mimetic resistance in lymphomas.
Scott BoikoTheresa ProiaMaryann San MartinGareth P GregoryMichelle Min WuNeeraj K AryalMaureen HattersleyWenlin ShaoJamal C SaehStephen E FawellRicky W JohnstoneLisa DrewJustin CidadoPublished in: Blood (2021)
BH3 mimetics like venetoclax target prosurvival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate that endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive to Mcl-1 and Bcl-2 inhibitors. However, suppression of Bfl-1 alone was insufficient to fully induce apoptosis in Bfl-1-expressing lymphomas, highlighting the need for targeting additional prosurvival proteins in this context. Importantly, we demonstrated that cyclin-dependent kinase 9 (CDK9) inhibitors rapidly downregulate both Bfl-1 and Mcl-1, inducing apoptosis in BH3-mimetic-resistant lymphoma cell lines in vitro and driving in vivo tumor regressions in diffuse large B-cell lymphoma patient-derived xenograft models expressing Bfl-1. These data underscore the need to clinically develop CDK9 inhibitors, like AZD4573, for the treatment of lymphomas using Bfl-1 as a selection biomarker.
Keyphrases
- diffuse large b cell lymphoma
- cell cycle
- epstein barr virus
- oxidative stress
- cell cycle arrest
- endoplasmic reticulum stress
- cell death
- liver failure
- poor prognosis
- small molecule
- stem cells
- big data
- bone marrow
- mesenchymal stem cells
- mechanical ventilation
- drug induced
- machine learning
- deep learning
- wild type
- respiratory failure
- pi k akt