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 <i>in vitro</i>. Thus, UAE is a promising target in lymphoid malignancies, including ibrutinib-resistant lymphomas, an area of unmet medical need.