Researchers characterized possible features of multiple myeloma (MM) cells that may be related to bortezomib (BTZ) resistance in patients with MM, in a new study published in the journal Cell Death and Disease.

MM is characterized by secretion of great quantities of immunoglobulins from B-lineage lymphocytes. Because of the possibility of producing misfolded proteins in this process, the researchers suggested, proteostasis may be a component of cellular adaptation that supports the survival of malignant cells in this condition. BTZ is a proteasome inhibitor that is used to treatment MM, which potentially disrupts this proteostasis system, thus reducing the viability of MM cells. However, drug resistance is seen with BTZ treatment, but mechanisms of resistance are not well understood, the study investigators indicated in their report.

A transcription factor called NRF1 may be involved in regulation of proteasome levels and function, the researchers also explained. A protease called DDI2 cleaves this factor, which enables activation of NRF1. DDI2 activity has been shown to play a role in the cytotoxicity of a proteasome inhibitor used in treatment of triple-negative breast cancer, the researchers noted. They undertook this study to evaluate possible relationships between NRF1, DDI2, and BTZ activity in MM cells.

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In this study, the researchers used MM cell lines altered to affect DDI2 expression levels, and they also developed a cell line model resistant to proteasome inhibitor therapy. They examined responses to BTZ therapy among cell lines and additionally assessed features related to NRF1 maturation.

In cells that were developed to be resistant to BTZ, DDI2 expression was elevated, with more cleavage of NRF1 when cells were treated with proteasome inhibitors. BTZ resistance also appeared to be maintained, indicating resistance was stable. However, when cells were stressed and then treated with BTZ, a deletion of DDI2 was associated with lower NRF1 maturation and restored susceptibility to BTZ. The researchers considered these results to suggest a possible contribution of DDI2 to BTZ adaptation.

In multiple MM cell lines that were deficient in DDI2 expression, BTZ sensitivity appeared to be enhanced. Additionally, in DDI2-deficient cells that had restoration of portions of DDI2, it became evident that 2 domains of DDI2, the helical domain of Ddi1 and the retroviral protease-like domain, were needed in order for NRF1 maturation to occur.

The researchers also found that nelfinavir, a protease inhibitor used in treatment of human immunodeficiency disease, appeared to provide partial inhibition of DDI2 in nelfinavir-treated cell lines, with NRF1 basal activation decreased in comparison with untreated cells. Such activity would represent an off-target effect of this agent, the researchers noted. MM cells treated with nelfinavir also appeared to be more sensitive to treatment with BTZ.

“Based on the genetic studies presented in this study, we can speculate that DDI2-specific drugs could restore responses to BTZ in resistant tumors,” the study investigators concluded in their report.


Op M, Ribeiro ST, Chavarria C, De Gassart A, Zaffalon L, Martinon F. The aspartyl protease DDI2 drives adaptation to proteasome inhibition in multiple myeloma. Cell Death Dis. 2022;13(5):475. doi:10.1038/s41419-022-04925-3