Macrophage migration inhibitory factor (MIF) is a novel regulator that influences sensitivity of multiple myeloma (MM) cells to proteasome inhibitors (PIs) and PI-containing treatments, which can lead to worse survival outcomes for patients with MM, according to research results published in Blood.
Even with modern advances in treatment, MM is difficult to treat, and drug resistance is a prominent problem in MM management. A team of investigators examined purified cells extracted from patients who had either relapsed or maintained responses to MM therapy, examined gene-profiling data from 1143 patients with MM to assess the importance of MIF in MM, and compared findings in mouse models to highlight mechanisms involved in the inhibition of PI sensitivity.
The researchers found that the expression of MIF was more abundant in cells from patients who had relapsed than cells from patients who had sustained responses. There also appeared to be a link between higher MIF expression and worse survival outcomes.
Additionally, MM cell lines showed greater amounts of MIF overall, while knockout of MIF enhanced sensitivity to proteasome inhibitor treatment. According to the researchers, MIF appears to suppress the production of superoxide in the presence of a proteasome inhibitor.
Biochemical analyses performed by the researchers suggested that MIF can behave as a chaperone of superoxide dismutase 1 (SOD1), protecting SOD1 from the misfolding that can result from contact with a proteasome inhibitor. This reportedly helps to preserve the normal superoxide-scavenging function of SOD1. Treatment with inhibitors of MIF in this study led to the misfolding of SOD1 and a loss of function when in the presence of a proteasome inhibitor. Furthermore, inhibition of MIF in vivo was associated with resensitization of MM cells to proteasome inhibitor treatment.
Using gene-profiling data, the researchers also found that there was a negative correlation between response to proteasome inhibitor therapy and expression of MIF and SOD1 among patients with MM.
The researchers concluded that MIF inhibition may be linked to sensitization of MM cells to proteasome inhibitor treatment. MIF inhibition has been examined in clinical trials with other tumor types, according to the researchers. “Therefore, treating MM by inhibiting MIF may be readily translatable in the clinic,” they wrote in their report. Additionally, they suggested that MIF is a potential biomarker for anticipating response to proteasome inhibitor therapy.
Wang Q, Zhao D, Xian M, et al. MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma [published online June 24, 2020]. Blood. doi: 10.1182/blood.2020005795