Novel mechanism of drug resistance to proteasome inhibitors in multiple myeloma

Abstract

Multiple myeloma (MM) is a cancer caused by uncontrolled proliferation of antibody-secreting plasma cells in bone marrow, which represents the second most common hematological malignancy. MM is a highly heterogeneous disease and can be classified into a spectrum of subgroups based on their molecular and cytogenetic abnormalities. In the past decade, novel therapies, especially, the first-in-class proteasome inhibitor bortezomib, have been revolutionary for the treatment of MM patients. Despite these remarkable achievements, myeloma remains incurable with a high frequency of patients suffering from a relapse, due to drug resistance. Mutation in the proteasome β5-subunit (PSMB5) was found in a bortezomib-resistant cell line generated via long-term coculture with increasing concentrations of bortezomib in 2008, but their actual implication in drug resistance in the clinic has not been reported until recently. A recent study discovered four resistance-inducing PSMB5 mutations from a relapsed MM patient receiving prolonged bortezomib treatment. Analysis of the dynamic clonal evolution revealed that two subclones existed at the onset of disease, while the other two subclones were induced. Protein structural modeling and functional assays demonstrated that all four mutations impaired the binding of bortezomib to the 20S proteasome, conferring different degrees of resistance. The authors further demonstrated two potential approaches to overcome drug resistance by using combination therapy for targeting proteolysis machinery independent of the 20S proteasome.

Keywords: Multiple myeloma; Proteasome inhibitor; Bortezomib; Proteasome β5-subunit; Drug resistance; Clonal evolution; Combination therapy

Core tip: Multiple myeloma (MM) is the second common hematological malignancy. An array of new treatments has been approved over the last decade. Hence, the survival of MM patients has improved steadily. Among these new drugs, the first-in-class proteasome inhibitor bortezomib has been revolutionary for targeted therapy. Now bortezomib is the backbone for treating MM. However, emerging drug resistance poses a major challenge for clinicians to use proteasome inhibitors. In this editorial, we discuss proteasome β5-subunit mutations as a novel resistant mechanism to bortezomib and its implication in tracking clonal evolution and suggest potential strategies to overcome drug resistance.