Proteasomal adaptations to FDA-approved proteasome inhibitors: A potential mechanism for drug resistance?

With proteasome inhibitors (PIs) becoming clinically available since 2003, outcomes for patients with multiple myeloma (MM) have dramatically changed, improving quality of life and survival. Despite the impressive treatment success, however, almost all MM patients who initially respond to these PIs eventually develop resistance. Furthermore, a portion of MM patients is inherently unresponsive to the PIs. Extensive mechanistic investigations identified several non-proteasomal signaling pathways suspected to be linked to the PI resistance, for which several excellent reviews are currently available. On the other hand, it is still unclear how cancer cells under high PI environments adapt to spare proteasome activity essential for survival and proliferation regardless of cancer evolution stages. This review outlines current progress towards understanding the proteasomal adaptations of cells in response to PI treatment to maintain necessary proteasome activity. A better understanding of cellular proteasomal changes in response to the PIs could provide a rationale to develop new therapeutics that could be used to overcome resistance to existing PI drugs.