BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia.

Autor:	Ramsey HE; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, Tennessee., Greenwood D; Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee., Zhang S; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee., Childress M; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee., Arrate MP; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee., Gorska AE; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee., Fuller L; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee., Zhao Y; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee., Stengel K; Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee., Fischer MA; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, Tennessee., Stubbs MC; Incyte Corporation, Wilmington, Delaware., Liu PCC; Incyte Corporation, Wilmington, Delaware., Boyd K; Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee., Rathmell JC; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, Tennessee.; Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.; Vanderbilt Center for Immunobiology, Nashville, Tennessee.; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee., Hiebert SW; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee., Savona MR; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. michael.savona@vumc.org.; Cancer Biology Program, Vanderbilt University School of Medicine, Nashville, Tennessee.; Vanderbilt Center for Immunobiology, Nashville, Tennessee.; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Jan 15; Vol. 27 (2), pp. 598-607. Date of Electronic Publication: 2020 Nov 04.
DOI:	10.1158/1078-0432.CCR-20-1346
Abstrakt:	Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal 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 venetoclax 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 venetoclax was assessed in cell lines and patient samples in vitro and in vivo 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 venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax 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 venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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