Why proteasome inhibitors cannot ERADicate multiple myeloma

Abstract

Proteasome inhibitors are key parts of our armamentarium against multiple myeloma, but the disease can become resistant through poorly defined mechanisms. In this issue of Cancer Cell, Leung-Hagesteijn and colleagues describe XBP1s(-) subpopulations of tumor cells that are resistant to bortezomib and may account for therapeutic failures in the clinic.

Figure 1. Model of proteasome inhibitor resistance from Tiedemann and colleagues

Patients with multiple myeloma may have a number of neoplastic subpopulations, including B-cells, activated B-cells, pre-plasmablasts, plasmablasts, and plasma cells. B-cells are typically cluster differentiation antigen 20⁺ (CD20⁺)/CD27⁺/paired box 5⁺ (PAX5⁺),and do not have spliced X-box binding protein 1 message XBP-1s^-), whereas activated B-cells are similar but express lower levels of CD20, and can be CD30⁺. Neither B-cells nor activated B-cells are involved in substantial immunoglobulin synthesis, and both therefore have relatively low levels of proteasome-assisted, endoplasmic reticulum-associated protein degradation(ERAD^lo). Pre-plasmablasts are probably CD27^lo/PAX5^lo/CD30⁺/XBP-1s^-, express the interleukin 6 receptor (IL-6R⁺), produce low levels of monoclonal protein (Y), and therefore have modest levels of ERAD activity (ERAD^mod). Plasmablasts are CD38⁺/CD138^lo/IL-6R⁺/XBP-1s⁺, secrete increased levels of monoclonal protein,and therefore have higher ERAD activity (ERAD^hi). Finally, terminally differentiated plasma cells are CD38⁺/CD138⁺/IL-6R⁺/XBP-1s⁺, produce high levels of monoclonal protein, and have the highest levels of ERAD activity. These phenotypic characteristics are taken from the work of Leung-Hagesteijn et al., and from other literature sources. Plasmablasts and plasma cells are sensitive to proteasome inhibitors such as bortezomib because of their high level of immunoglobulin synthesis, leading to high levels of ERAD-related stress, which triggers dependence on the unfolded protein response (UPR). B-cells, activated B-cells, and pre-plasmablasts, in part because they are XBP-1s^-, produce less immunoglobulin, and are therefore less susceptible. Treatment with bortezomib eradicates plasmablasts and plasma cells, which initially may make up the bulk of the tumor compartment, and results in elimination of the monoclonal protein marker. However, B-cells, activated B-cells, and pre-plasmablasts,which initially are a minor component of the tumor compartment, survive. After expansion of these cells, patients may then develop clinical relapses that are bortezomib-resistant with diseasethat ishypo- or non-secretory, and may require a different treatment approach.