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The aspartyl protease DDI2 drives adaptation to proteasome inhibition in multiple myeloma

Mélanie Op¹, Sérgio T Ribeiro¹, Claire Chavarria¹

¹Department of Immunobiology, University of Lausanne, 155 Ch. des Boveresses, 1066, Epalinges, Switzerland.

Cell Death & Disease

|May 19, 2022

Abstract:

Proteasome inhibitors, such as bortezomib, are first-line therapy against multiple myeloma (MM). Unfortunately, patients frequently become refractory to this treatment. The transcription factor NRF1 has been proposed to initiate an adaptation program that regulates proteasome levels. In the context of proteasome inhibition, the cytosolic protease DDI2 cleaves NRF1 to release an active fragment that translocates to the nucleus to promote the transcription of new proteasome subunits. However, the contribution of the DDI2-NRF1 pathway to bortezomib resistance is poorly understood. Here we show that upon prolonged bortezomib treatment, MM cells become resistant to proteasome inhibition by increasing the expression of DDI2 and consequently activation of NRF1. Furthermore, we found that many MM cells became more sensitive to proteasome impairment in the context of DDI2 deficiency. Mechanistically, we demonstrate that both the protease and the HDD domains of DDI2 are required to activate NRF1. Finally, we show that partial inhibition of the DDI2-protease domain with the antiviral drug nelfinavir increased bortezomib susceptibility in treated MM cells. Altogether, these findings define the DDI2-NRF1 pathway as an essential program contributing to proteasome inhibition responses and identifying DDI2 domains that could be targets of interest in bortezomib-treated MM patients.

Insights

Multiple myeloma cells resist bortezomib by activating the DDI2-NRF1 pathway. Inhibiting DDI2 enhances bortezomib effectiveness, offering new therapeutic strategies for resistant multiple myeloma.

Area of Science:

Molecular Biology
Cancer Biology
Pharmacology

Background:

Proteasome inhibitors like bortezomib are crucial for multiple myeloma (MM) treatment.
Therapeutic resistance to bortezomib is a significant clinical challenge in MM.
The DDI2-NRF1 pathway regulates proteasome adaptation but its role in bortezomib resistance is unclear.

Purpose of the Study:

To investigate the role of the DDI2-NRF1 pathway in bortezomib resistance in multiple myeloma.
To identify mechanisms by which DDI2-NRF1 contributes to therapeutic adaptation.
To explore DDI2 as a potential therapeutic target to overcome bortezomib resistance.

Main Methods:

Cell culture models of multiple myeloma.
Analysis of gene expression and protein activation.
Functional assays assessing cell viability and proteasome activity.
Inhibition studies using small molecules and genetic manipulation.

Main Results:

Prolonged bortezomib treatment increases DDI2 expression and NRF1 activation in MM cells, conferring resistance.
DDI2 deficiency sensitizes MM cells to proteasome impairment.
Both protease and HDD domains of DDI2 are essential for NRF1 activation.
The antiviral drug nelfinavir, by inhibiting DDI2, enhances bortezomib susceptibility.

Conclusions:

The DDI2-NRF1 pathway is a key adaptive mechanism driving bortezomib resistance in multiple myeloma.
Targeting DDI2, particularly its protease domain, represents a promising strategy to enhance bortezomib efficacy in resistant MM.
DDI2 inhibition could overcome therapeutic resistance and improve patient outcomes.

Read full analysis

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