Abstract
With the advent of proteasome inhibitors (bortezomib) and pleiotropic pathway modulators which target cereblon E3 ligase (lenalidomide), the ubiquitin-proteasome system has emerged as a tractable target in non-Hodgkin lymphoma and multiple myeloma. Here we report that TAK-243, a small molecule inhibitor of the ubiquitin-activating enzyme (UAE), induced ER stress and the unfolded protein response in primary chronic lymphocytic leukemia cells, facilitating cell death. Moreover, targeting UAE was effective in ibrutinib-resistant mantle cell lymphoma cell lines and primary cells in vitro. Thus, UAE is a promising target in lymphoid malignancies, including ibrutinib-resistant lymphomas, an area of unmet medical need.
Keywords:
CLL; TAK-243; Ubiquitin-activating enzyme.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Animals
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Apoptosis / drug effects*
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Biomarkers
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Cell Line, Tumor
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Drug Resistance, Neoplasm*
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Endoplasmic Reticulum Stress / drug effects*
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Lymphoma, Mantle-Cell / diagnosis
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Lymphoma, Mantle-Cell / drug therapy
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Lymphoma, Mantle-Cell / metabolism*
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Mice
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Piperidines
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Proteasome Inhibitors / pharmacology
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Proteasome Inhibitors / therapeutic use
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Protein Kinase Inhibitors / therapeutic use
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Pyrazoles / pharmacology*
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Pyrazoles / therapeutic use
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Pyrimidines / pharmacology*
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Pyrimidines / therapeutic use
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Ubiquitin-Activating Enzymes / metabolism*
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Unfolded Protein Response / drug effects
Substances
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Biomarkers
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Piperidines
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Proteasome Inhibitors
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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ibrutinib
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Ubiquitin-Activating Enzymes
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Adenine