Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Bortezomib is an effective multiple myeloma (MM) therapy but faces challenges with toxicity and resistance.
• Targeting ubiquitin receptors upstream of the 20S proteasome offers a strategy for developing less toxic MM therapies.
• Rpn13 is a 19S proteasome-associated ubiquitin receptor overexpressed in MM cells.

Purpose of the Study:

• To investigate the therapeutic potential of targeting Rpn13 in multiple myeloma (MM).
• To evaluate a novel Rpn13-targeting agent, RA190, for its efficacy and safety in preclinical MM models.
• To explore combination strategies involving RA190 for improved MM treatment outcomes.

Main Methods:

• Investigated Rpn13 expression in MM cells versus normal plasma cells.
• Utilized Rpn13-siRNA and CRISPR/Cas9 Rpn13-knockout to assess Rpn13 dependency.
• Evaluated the anti-MM activity of RA190 in cell lines, patient cells, and a xenograft model.
• Assessed mechanisms of action including apoptosis induction and combination effects.

Main Results:

• Rpn13 is highly expressed in MM cells; Rpn13-siRNA reduces MM cell viability.
• RA190 targets Rpn13, inhibits proteasome function, decreases MM cell viability, and overcomes bortezomib resistance.
• RA190 induces caspase-dependent and UPR-related apoptosis, is well-tolerated in vivo, inhibits tumor growth, and prolongs survival.
• RA190 demonstrates synergistic activity when combined with bortezomib, lenalidomide, or pomalidomide.

Conclusions:

• Targeting Rpn13 is a validated strategy to overcome bortezomib resistance in multiple myeloma (MM).
• RA190 is a promising Rpn13 inhibitor with preclinical efficacy and tolerability for MM treatment.
• These findings support the clinical evaluation of Rpn13 inhibitors for improving MM patient outcomes.