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

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2947-2957
Number of pages11
JournalBlood
Volume137
Issue number21
DOIs
Publication statusPublished - 27 May 2021

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