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Chronic lymphocytic leukemia

The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment

Leukemia volume 34, pages 1588–1598 (2020)Cite this article

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Abstract

Despite major improvements in treatment outcome with novel targeted therapies, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, chronic lymphocytic leukemia (CLL) remains incurable in the majority of patients. Activation of PI3K, NF-κB, and/or MYC has been linked to residual disease and/or resistance in ibrutinib-treated patients. These pathways can be targeted by inhibitors of bromodomain and extra-terminal (BET) proteins. Here we report about the preclinical activity of GS-5829, a novel BET inhibitor, in CLL. GS-5829 inhibited CLL cell proliferation and induced leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. IκBα modulation indicates that GS-5829 also inhibited NF-κB signaling. GS-5829-induced apoptosis resulted from an imbalance between positive (BIM) and negative regulators (BCL-XL) of the intrinsic apoptosis pathway. The antileukemia activity of GS-5829 increased synergistically in combinations with B-cell receptor signaling inhibitors, the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, and the SYK inhibitor entospletinib. In cocultures that mimic the lymph node microenvironment, GS-5829 inhibited signaling pathways within nurselike cells and their growth, indicating that BET inhibitors also can target the supportive CLL microenvironment. Collectively, these data provide a rationale for the clinical evaluation of BET inhibitors in CLL.

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Fig. 1: GS-5829 induces apoptosis and suppresses proliferation of CLL cells.
Fig. 2: GS-5829 and ibrutinib synergistically induce apoptosis of primary CLL cells irrespective of their IGHV mutational status and ZAP-70 expression.
Fig. 3: GS-5829 and the BCR signaling inhibitors ibrutinib, idelalisib, and entospletinib synergistically induce CLL cell apoptosis.
Fig. 4: GS-5829 changes the levels of multiple proteins in CLL.
Fig. 5: GS-5829 also targets CLL nurselike cells in CLL/NLC cocultures.
Fig. 6: Effects of GS-5829 on signaling in NLC.

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Acknowledgements

This study was supported in part by MD Anderson’s CLL Moonshot program, MD Anderson’s Cancer Center Support grant P30 CA016672 and Gilead Sciences, Inc. EtH is a Special Fellow of the Leukemia and Lymphoma Society. The BET inhibitor GS-5829 was provided by Gilead Sciences, Inc.

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ekaterina Kim, Mariela Sivina, Philip A. Thompson, Nitin Jain, Alessandra Ferrajoli, Zeev Estrov, Michael J. Keating, William G. Wierda, Kapil N. Bhalla & Jan A. Burger

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Elisa ten Hacken

  3. Gilead Sciences, Inc, Seattle, WA, USA

    Astrid Clarke

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Correspondence to Jan A. Burger.

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Conflict of interest

AC is an employee of Gilead Sciences, Inc. and owns equity in the company; PAT has served as a consultant for AbbVie and Pharmacyclics, an AbbVie company; NJ has served as a consultant for AbbVie, Pharmacyclics, and Janssen Pharmaceuticals, Inc. and received research funding from Pharmacyclics; WGW has received honoraria, served as a consultant and received research funding from Gilead Sciences, Inc.; JAB has received research funding from Gilead Sciences and Pharmacyclics, travel expenses from Gilead Sciences and served as a consultant for Janssen Pharmaceuticals. The remaining authors declare no competing interests. The BET inhibitor GS-5829, idelalisib, and entospletinib were provided by Gilead Sciences, Inc.

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Kim, E., ten Hacken, E., Sivina, M. et al. The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment. Leukemia 34, 1588–1598 (2020). https://doi.org/10.1038/s41375-019-0682-7

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