BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression.

Autor:	Cummin TEC; Antibody and Vaccine Group, Centre for Cancer Immunology., Cox KL; Antibody and Vaccine Group, Centre for Cancer Immunology., Murray TD; Antibody and Vaccine Group, Centre for Cancer Immunology., Turaj AH; Antibody and Vaccine Group, Centre for Cancer Immunology., Dunning L; Preclinical Unit, Centre for Cancer Immunology, and., English VL; Preclinical Unit, Centre for Cancer Immunology, and., Fell R; Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; and., Packham G; Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; and., Ma Y; Plexxikon Inc., Berkeley, CA., Powell B; Plexxikon Inc., Berkeley, CA., Johnson PWM; Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; and., Cragg MS; Antibody and Vaccine Group, Centre for Cancer Immunology., Carter MJ; Antibody and Vaccine Group, Centre for Cancer Immunology.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2020 Jul 28; Vol. 4 (14), pp. 3316-3328.
DOI:	10.1182/bloodadvances.2020002231
Abstrakt:	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. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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