PB2115 NRF1‐DEPENDENT PATHWAY: SALVAGE PATHWAY AFTER THE PROTEASOME INHIBITION IN MULTIPLE MYELOMA AND MANTLE CELL LYMPHOMA?

Abstract

Background:Proteasome inhibitors (PI) are compounds with anti‐neoplastic effect in various hematological cancers. Bortezomib, the first FDA approved PI compound, represents the backbone therapy in case of multiple myeloma (in the first line therapy and in relapse) and has proven efficacy in mantle cell lymphoma. However, the resistance to proteasome inhibitor treatment often occurs and limits the possibility of subsequent therapy. The mechanism of resistance to PI is not fully understood. Usually, it is associated with high expression of proteasome subunits or, in some cases, could be caused by mutations in proteasome subunits that hinder the binding site of the inhibitor. One of the homeostasis pathways that regulates the synthesis of proteasome subunits is the nuclear factor erythroid‐derived 2 related factor 1 (Nrf1)‐dependent pathway. Nrf1 is a transcription factor responsible for the regulation of the genes involved in protecting cells from oxidative stress and regulating proteasomal activity. In normal conditions, it is embedded in the membrane of endoplasmatic reticulum, retrotranslocated by VCP/p97 complex to cytosol, deglycosylated and processed by proteasome. However, when proteasome is inhibited, Nrf1 is cleaved by DDI2 protease, becomes active and acts as a transcription factor in the nucleus where it upregulates the synthesis of the proteasome.Aims:Evaluation of the roles of individual factors of Nrf1‐dependent pathway under the PI treatment of hematologic neoplasias.MethodsThe cell lines with various sensitivity to PI generated from various hematologic neoplasias (mainly multiple myeloma, mantle cell lymphoma) were treated by several PIs and the levels and forms of the components in the Nrf1‐dependent pathway were measured.Results:The presence of the Nrf1‐dependent pathway components in hematologic neoplasia was confirmed. The PI treatment in the majority of cell lines led to the increase of the levels of the activated form of Nrf1 while the DDI2 levels did not significantly change.Summary/Conclusion:The activation of the Nrf1‐dependent pathway responsible for the proteasomal units expression after the PI treatment in hematologic neoplasia derived cells suggests that the inhibition of this pathway can improve the sensitivity to PI and might potentially open up new approaches to the PI refractory disease therapy.