TY - JOUR
T1 - The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment
AU - Kim, Ekaterina
AU - ten Hacken, Elisa
AU - Sivina, Mariela
AU - Clarke, Astrid
AU - Thompson, Philip A.
AU - Jain, Nitin
AU - Ferrajoli, Alessandra
AU - Estrov, Zeev
AU - Keating, Michael J.
AU - Wierda, William G.
AU - Bhalla, Kapil N.
AU - Burger, Jan A.
N1 - Funding Information:
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.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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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U2 - 10.1038/s41375-019-0682-7
DO - 10.1038/s41375-019-0682-7
M3 - Article
C2 - 31862959
AN - SCOPUS:85077060234
SN - 0887-6924
VL - 34
SP - 1588
EP - 1598
JO - Leukemia
JF - Leukemia
IS - 6
ER -