Proteasome inhibitors in cancer therapy

Abstract

The proteasome is a central component of the protein degradation machinery in eukaryotic cells Both transformed and normal cells depend on the function of the proteasome to control the expression of proteins linked to cell survival and proliferation Clinical trials using proteasome inhibitors in myeloma, mantle-cell lymphoma (MCL) and amyloidosis have transformed the treatment of these diseases by establishing new standards of care Three proteasome inhibitors have received regulatory approval and are used routinely in clinical settings, including bortezomib, carfilzomib and ixazomib Primary resistance to proteasome inhibitors remains a challenge in patients with solid tumours; in addition, acquired resistance can be developed in myeloma and MCL even after initial responses, through mechanisms that are beginning to be understood Clinical evaluation of compounds targeting the upstream regulatory components of the proteasome is underway; in the future, compounds that target proteasome-mediated degradation of specific proteins might also become available