Lessons Learned from Proteasome Inhibitors, the Paradigm for Targeting Protein Homeostasis in Cancer.

Targeting aberrant protein homeostasis (proteostasis) in cancer is an attractive therapeutic strategy. However, this approach has thus far proven difficult to bring to clinical practice, with one major exception: proteasome inhibition. These small molecules have dramatically transformed outcomes for patients with the blood cancer multiple myeloma. However, these agents have failed to make an impact in more common solid tumors. Major questions remain about whether this therapeutic strategy can be extended to benefit even more patients. Here we discuss the role of the proteasome in normal and tumor cells, the basic, preclinical, and clinical development of proteasome inhibitors, and mechanisms proposed to govern both intrinsic and acquired resistance to these drugs. Years of study of both the mechanism of action and modes of resistance to proteasome inhibitors reveal these processes to be surprisingly complex. Here, we attempt to draw lessons from experience with proteasome inhibitors that may be relevant for other compounds targeting proteostasis in cancer, as well as extending the reach of proteasome inhibitors beyond blood cancers.