BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells


Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-κB (NF-κB) 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-κB 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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We thank the Flow Cytometry and Cellular Imaging (FCCI) Core Facility and the Functional Proteomics RPPA Core facility that are supported by MD Anderson Cancer Center Support Grant 5P30 CA016672-40. The RPPA heatmaps were developed by the MD Anderson Cancer Center Department of Bioinformatics and Computational Biology, In Silico Solutions, Santeon and SRA International. This work was supported in part by US National Cancer Institute (NCI; MD Anderson TCGA Genome Data Analysis Center) Grant Numbers CA143883 and CA083639, the Mary K Chapman Foundation, the Michael & Susan Dell Foundation (honoring Lorraine Dell) and MD Anderson Cancer Center Support Grant P30 CA016672 (the Bioinformatics Shared Resource). This project was partially supported by CPRIT RP170295 (to CC), the shared Proteomics and Metabolomics core at Baylor College of Medicine with funding from the NIH (P30 CA125123), CPRIT Proteomics and Metabolomics Core Facility RP120092 (to KR and CC) and the NCI-recognized Dan L Duncan Cancer Center. CMC acknowledges support from the National Institutes of Health (Grant Number R35 CA197589).

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Correspondence to K N Bhalla.

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CMC is the founder and Chief Scientific Advisor of, and possesses an equity ownership stake in, Arvinas, Inc. YQ, KR, KGC, APC and AS are Arvinas employees and possess an equity ownership stake in Arvinas. The other authors state declare no conflict of interest.

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Sun, B., Fiskus, W., Qian, Y. et al. BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. Leukemia 32, 343–352 (2018).

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