BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression
| العنوان: | BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression |
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| المؤلفون: | Rachel Fell, Kerry L. Cox, Mark S. Cragg, Thomas Cummin, Peter Johnson, Anna H. Turaj, Lisa Dunning, Tom D Murray, Matthew J. Carter, Vikki English, Graham Packham, Yan Ma, Ben Powell |
| المصدر: | Blood Adv |
| بيانات النشر: | American Society of Hematology, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Programmed cell death, Pyridines, Apoptosis, Nerve Tissue Proteins, Receptors, Cell Surface, Biology, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Downregulation and upregulation, In vivo, Cell Line, Tumor, hemic and lymphatic diseases, medicine, Animals, Pyrroles, Oxazoles, Psychological repression, Sulfonamides, Lymphoid Neoplasia, Venetoclax, Hematology, Bridged Bicyclo Compounds, Heterocyclic, medicine.disease, Lymphoma, Bromodomain, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, chemistry, 030220 oncology & carcinogenesis, Cancer research |
| الوصف: | Although the MYC oncogenic network represents an attractive therapeutic target for lymphoma, MYC inhibitors have been difficult to develop. Alternatively, inhibitors of epigenetic/ transcriptional regulators, particularly the bromodomain and extraterminal (BET) family, have been used to modulate MYC. However, current benzodiazepine-derivative BET inhibitors (BETi) elicit disappointing responses and dose-limiting toxicity in relapsed/refractory lymphoma, potentially because of enrichment of high-risk molecular features and chemical backbone-associated toxicities. Consequently, novel nonbenzodiazepine BETi and improved mechanistic understanding are required. Here we characterize the responses of aggressive MYC-driven lymphomas to 2 nonbenzodiazepine BETi: PLX51107 and PLX2853. Both invoked BIM-dependent apoptosis and in vivo therapy, associated with miR-17∼92 repression, in murine Eµ-myc lymphomas, with PLX2853 exhibiting enhanced potency. Accordingly, exogenous BCL-2 expression abrogated these effects. Because high BCL-2 expression is common in diffuse large B-cell lymphoma (DLBCL), BETi were ineffective in driving apoptosis and in vivo therapy of DLBCL cell lines, mirroring clinical results. However, BETi-mediated BIM upregulation and miR-17∼92 repression remained intact. Consequently, coadministration of BETi and ABT199/venetoclax restored cell death and in vivo therapy. Collectively, these data identify BIM-dependent apoptosis as a critical mechanism of action for this class of BETi that, via coadministration of BH3 mimetics, can deliver effective tumor control in DLBCL. |
| وصف الملف: | text |
| تدمد: | 2473-9537 2473-9529 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::64c7b9768ccf26053b1ab4dec84131daTest https://doi.org/10.1182/bloodadvances.2020002231Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....64c7b9768ccf26053b1ab4dec84131da |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 24739537 24739529 |
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