Journal
LEUKEMIA
Volume 32, Issue 2, Pages 343-352Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2017.207
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Funding
- MD Anderson Cancer Center Support Grant [5P30 CA016672-40, P30 CA016672]
- US National Cancer Institute (NCI
- MD Anderson TCGA Genome Data Analysis Center) [CA143883, CA083639]
- Mary K Chapman Foundation
- Michael & Susan Dell Foundation
- CPRIT [RP170295]
- NIH [P30 CA125123]
- CPRIT Proteomics and Metabolomics Core Facility [RP120092]
- NCI-recognized Dan L Duncan Cancer Center
- National Institutes of Health [R35 CA197589]
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Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-kappa B (NF-kappa B) target genes that undermines the growth and survival of mantle cell lymphoma (MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-kappa B transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior preclinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or -resistant MCL.
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