Targeting Bfl-1 via acute CDK9 inhibition overcomes intrinsic BH3-mimetic resistance in lymphomas

Boiko, S; Proia, T; San Martin, M; Gregory, GP; Wu, MM; Aryal, N; Hattersley, M; Shao, W; Saeh, JC; Fawell, SE; Johnstone, RW; Drew, L; Cidado, J

Author(s): Boiko, S; Proia, T; San Martin, M; Gregory, GP; Wu, MM; Aryal, N; Hattersley, M; Shao, W; Saeh, JC; Fawell, SE; Johnstone, RW; Drew, L; Cidado, J;
Details: Publication Year 2021-05-27,Volume 137,Issue #21,Page 2947-2957
Journal Title: Blood
Publication Type: Research article
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.
Keywords: Animals; Antineoplastic Agents/pharmacology; Bridged Bicyclo Compounds, Heterocyclic/*pharmacology/therapeutic use; Cell Line, Tumor; Cyclin-Dependent Kinase 9/*antagonists & inhibitors/physiology; Cycloheximide/pharmacology; Drug Resistance, Neoplasm/*drug effects; Female; Gene Expression Regulation, Neoplastic/drug effects; Humans; Leupeptins/pharmacology; Lymphoma, Large B-Cell, Diffuse/*drug therapy; Macrocyclic Compounds/*pharmacology/therapeutic use; Mice; Mice, Inbred NOD; Mice, SCID; Minor Histocompatibility Antigens/biosynthesis/genetics; *Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein/biosynthesis/genetics; Neoplasm Proteins/*antagonists & inhibitors/biosynthesis/genetics; Peptide Fragments/antagonists & inhibitors; Piperazines/pharmacology; Proto-Oncogene Proteins/antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2/*antagonists & inhibitors/biosynthesis/genetics; Pyridines/pharmacology; Sulfonamides/*pharmacology/therapeutic use; Xenograft Model Antitumor Assays
Department(s): Laboratory Research
PubMed ID: 33259592
Publisher's Version: https://doi.org/10.1182/blood.2020008528
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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