Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?

SIMPLE SUMMARY: Advances in treatment, especially with novel drugs, have dramatically improved the survival of multiple myeloma (MM) patients recently. However, frequent relapses and drug resistance remain unsolved issues. Endoplasmic reticulum stress (ERS) is elevated in MM compared to normal plasma cells, and is regarded as the Achilles’ heel of MM. This review summarizes the current knowledge of how ERS response influences the pathogenesis and drug-resistance of MM, and provides inspiration for novel therapeutic strategies to improve clinical outcomes of MM patients by targeting ERS. ABSTRACT: Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.