BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia
- 15 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 27 (2), 598-607
- https://doi.org/10.1158/1078-0432.ccr-20-1346
Abstract
Purpose: The BCL2 inhibitor, venetoclax (VEN), has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. VEN-based regimens can potentially lead to marrow suppression. Bromodomain and extra-terminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with VEN to reduce AML without induction of hematopoietic toxicity. Experimental Design: INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line derived xenografts. Precision run-on and sequencing (PRO-Seq) evaluated effects of INCB054329. Synergy between low dose BETi and VEN was assessed in cell lines and patient samples while efficacy and toxicity was assessed in patient derived xenograft (PDX) models. Results: INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-Seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and VEN led to reduced cell viability in cell lines and patient samples. Low dose combinations of INCB054329 and VEN in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity. Conclusions: Our findings suggest low dose combinations of VEN and BETi may be more efficacious for AML patients than either monotherapy, potentially providing a longer, more tolerable dosing regimen.Keywords
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Funding Information
- NIH (P30 CA068485-19)
- NIH NCATS (UL1 TR000445)
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