Clinical experience on proteasome inhibitors in cancer

The ubiquitin-proteasome system (UPS) plays a central role in cellular protein homeostasis, through the targeted destruction of regulatory proteins and damaged or misfolded proteins, typically exacerbated in cancer cells, as a result of genomic aberrations and/or mutations. The UPS controls critical cellular functions which impact tumor and immune effector cell biology. Over the last two to three decades, proteasome inhibition became recognized as an anti-cancer therapy, with several first- and second-generation agents approved in multiple myeloma, where they became the cornerstone of current regimens. First-in-class bortezomib was also approved in amyloidosis, mantle cell lymphoma, Waldenstrom's macroglobulinemia, and ATLL (Adult T-cell leukemia/lymphoma). On the other hand, in solid tumors, and despite robust pre-clinical rationale, the clinical activity of proteasome inhibition remains very limited with no approved indications. Although the mechanisms of resistance to proteasome inhibitors are not fully elucidated, significant progress in understanding the UPS pathway suggests greater opportunities in the future for targeting proteins degradation, well beyond the 20S core unit, in cancer and also autoimmune diseases, degenerative diseases, and aging.