The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors

The destruction of proteins via the ubiquitin-proteasome system is a multi-step, complex process involving polyubiquitination of substrate proteins, followed by proteolytic degradation by the macromolecular 26S proteasome complex. Inhibitors of the proteasome promote the accumulation of proteins that are deleterious to cell survival, and represent promising anti-cancer agents. In multiple myeloma and mantle cell lymphoma, treatment with the first-generation proteasome inhibitor, bortezomib, or the second-generation inhibitor, carfilzomib, has demonstrated significant therapeutic benefit in humans. This has prompted United States Food and Drug Administration (US FDA) approval of these agents and development of additional second-generation compounds with improved properties. There is considerable interest in extending the benefits of proteasome inhibitors to the treatment of solid tumor malignancies. Herein, we review progress that has been made in the preclinical development and clinical evaluation of different proteasome inhibitors in solid tumors. In addition, we describe several novel approaches that are currently being pursued for the treatment of solid tumors, including drug combinatorial strategies incorporating proteasome inhibitors and the targeting of components of the ubiquitin-proteasome system that are distinct from the 26S proteasome complex.