Proteasome inhibitor bortezomib is an effective
therapy for relapsed and newly diagnosed
multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance can limit its long-term utility. Recent research has focused on targeting
ubiquitin receptors upstream of
20S proteasome, with the aim of generating less toxic
therapies. Here we show that 19S
proteasome-associated
ubiquitin receptor Rpn13 is more highly expressed in MM cells than in normal plasma cells. Rpn13-siRNA (
small interfering RNA) decreases MM cell viability. A novel agent
RA190 targets Rpn13 and inhibits
proteasome function, without blocking the
proteasome activity or the 19S deubiquitylating activity. CRISPR/Cas9 Rpn13-knockout demonstrates that RA190-induced activity is dependent on Rpn13.
RA190 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma and overcomes
bortezomib resistance. Anti-MM activity of
RA190 is associated with induction of caspase-dependent apoptosis and unfolded protein response-related apoptosis. MM xenograft model studies show that
RA190 is well tolerated, inhibits
tumor growth and prolongs survival. Combining
RA190 with
bortezomib,
lenalidomide or
pomalidomide induces synergistic anti-MM activity. Our preclinical data validates targeting Rpn13 to overcome
bortezomib resistance, and provides the framework for clinical evaluation of Rpn13 inhibitors, alone or in combination, to improve patient outcome in MM.