Endoplasmic reticulum stress and proteasome inhibitors in multiple myeloma: room for improvement

In the last 2 decades, we witnessed unprecedented progress in multiple myeloma research. The median survival times doubled, and with the introduction of subsequent new therapeutics, we expect even better results in the nearest future. However, the disease still remains incurable. It is attributed to recurring nature of multiple myeloma with reappearance of subclones resistant to previously used therapies. More than 15 years after the approval of the first‑in‑class proteasome inhibitor, bortezomib, the mechanisms responsible for resistance to this class of drugs are still not fully elucidated. One of the most promising explanations involves modulation of endoplasmic reticulum stress caused by accumulation of misfolded proteins. Due to excessive monoclonal protein production, multiple myeloma cells are particularly susceptible to proteotoxicity. Under normal circumstances, they counteract it with activation of an adaptive mechanism, that is, the unfolded protein response. This pathway, however, can also lead to cell apoptosis when unable to restore proteostasis. It is the expected effect of proteasome inhibition. Resistant cells develop mechanisms that decrease the endoplasmic reticulum stress. This review covers current efforts to understand the nature of this adaptation. It focuses on druggable targets that can potentially enhance proteasome inhibitors activity or resensitize resistant patients to this type of therapy.