Journal
BLOOD
Volume 137, Issue 21, Pages 2947-2957Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020008528
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Funding
- Cancer Council Victoria
- National Health and Medical Research Council Australia
- Peter MacCallum Cancer Foundation
- Kids Cancer Project [AZ'5576]
- AstraZeneca
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BH3 mimetics like venetoclax target prosurvival Bcl-2 family proteins and are important therapeutics for hematological malignancies. The study shows that CDK9 inhibitors can rapidly downregulate Bfl-1 and Mcl-1, inducing apoptosis in BH3-mimetic-resistant lymphoma cell lines in vitro and driving tumor regressions in patient-derived xenograft models expressing Bfl-1. This highlights the potential of CDK9 inhibitors, such as AZD4573, for the treatment of lymphomas with Bfl-1 as a selection biomarker.
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.
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