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Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma.

Y Song1, A Ray1, S Li2

  • 1LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Leukemia
|April 28, 2016
PubMed
Summary
This summary is machine-generated.

A novel drug RA190 targets Rpn13 to treat multiple myeloma (MM), overcoming bortezomib resistance. This Rpn13 inhibitor shows promise as a less toxic therapy for MM patients.

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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.