Targeting Bfl-1 via acute CDK9 inhibition overcomes intrinsic BH3-mimetic resistance in lymphomas
Scott Boiko, Theresa Proia, Maryann San Martin, Gareth P Gregory, Michelle Min Wu, Neeraj Aryal, Maureen Hattersley, Wenlin Shao, Jamal C Saeh, Stephen E Fawell, Ricky W Johnstone, Lisa Drew, Justin Cidado
BLOOD | AMER SOC HEMATOLOGY | Published : 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 ..View full abstract
Awarded by Kids Cancer Project
The contributions from G.P.G. and R.W.J. were supported by grants from the Cancer Council Victoria, National Health and Medical Research Council Australia, The Peter MacCallum Cancer Foundation, and The Kids Cancer Project. AZ'5576 was provided to G.P.G. and R.W.J. under MTA agreement with AstraZeneca.