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Overcoming Bortezomib Resistance

Inhibitors of the proteasome—an intracellular enzyme complex that regulates intracellular protein levels by degrading those tagged with ubiquitin—have demonstrated clinical efficacy in the treatment of multiple myeloma and mantle cell lymphoma and are being evaluated for the treatment of other malignancies. Bortezomib—the only reversible proteasome inhibitor approved by the US Food and Drug Administration—improves clinical outcomes when used as a single agent. However, most patients do not respond to this drug and those who do respond usually relapse. Proteasome inhibitors that bind the active site of the proteasome and inhibit the complex irreversibly are in advanced clinical trials. Inhibitors that act on sites of the proteasome outside of the catalytic center are in preclinical development. Ruschak et al. (p. 1007 ) review the structure and function of the proteasome. They focus on the molecular biology, chemistry, and the preclinical and clinical efficacy of novel proteasome inhibitors as strategies to inhibit this target and overcome some forms of bortezomib resistance.