Pharmacologic inhibition of the ubiquitin-activating enzyme induces ER stress and apoptosis in chronic lymphocytic leukemia and ibrutinib-resistant mantle cell lymphoma cells.

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.

• Authors: Scott Best, Tingting Liu, Nur Bruss, Adam Kittai, Allison Berger, Alexey V Danilov
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 60 Issue 12 Pg. 2946-2950 (12 2019) ISSN: 1029-2403 [Electronic] United States
• PMID: 31111763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Piperidines
• Proteasome Inhibitors
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• ibrutinib
• Ubiquitin-Activating Enzymes
• Adenine

Topics

• Adenine (analogs & derivatives)
• Animals
• Apoptosis (drug effects)
• Biomarkers
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (diagnosis, drug therapy, metabolism)
• Lymphoma, Mantle-Cell (diagnosis, drug therapy, metabolism)
• Mice
• Piperidines
• Proteasome Inhibitors (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (therapeutic use)
• Pyrazoles (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Ubiquitin-Activating Enzymes (metabolism)
• Unfolded Protein Response (drug effects)