Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Sep 24, 2019; 10(9): 303-306
Published online Sep 24, 2019. doi: 10.5306/wjco.v10.i9.303
Novel mechanism of drug resistance to proteasome inhibitors in multiple myeloma
Jianbiao Zhou, Wee-Joo Chng
Jianbiao Zhou, Wee-Joo Chng, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Singapore
Jianbiao Zhou, Wee-Joo Chng, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
Wee-Joo Chng, Department of Hematology-Oncology, National University Cancer Institute, NUHS, Singapore 119228, Singapore
Author contributions: Zhou JB and Chng WJ reviewed the literature and wrote the manuscript.
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Jianbiao Zhou, MD, PhD, Senior Scientist, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 28 Medical Drive, Singapore 117456, Singapore. csizjb@nus.edu.sg
Telephone: +65-65161118 Fax: +65-68739664
Received: March 19, 2019
Peer-review started: March 19, 2019
First decision: August 2, 2019
Revised: August 14, 2019
Accepted: August 21, 2019
Article in press: August 21, 2019
Published online: September 24, 2019

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.