Different Strategies to Overcome Resistance to Proteasome Inhibitors-A Summary 20 Years after Their Introduction

Abstract

Proteasome inhibitors (PIs), bortezomib, carfilzomib, and ixazomib, are the first-line treatment for multiple myeloma (MM). They inhibit cytosolic protein degradation in cells, which leads to the accumulation of misfolded and malfunctioned proteins in the cytosol and endoplasmic reticulum, resulting in cell death. Despite being a breakthrough in MM therapy, malignant cells develop resistance to PIs via different mechanisms. Understanding these mechanisms drives research toward new anticancer agents to overcome PI resistance. In this review, we summarize the mechanism of action of PIs and how MM cells adapt to these drugs to develop resistance. Finally, we explore these mechanisms to present strategies to interfere with PI resistance. The strategies include new inhibitors of the ubiquitin-proteasome system, drug efflux inhibitors, autophagy disruption, targeting stress response mechanisms, affecting survival and cell cycle regulators, bone marrow microenvironment modulation, and immunotherapy. We list potential pharmacological targets examined in in vitro, in vivo, and clinical studies. Some of these strategies have already provided clinicians with new anti-MM medications, such as panobinostat and selinexor. We hope that further exploration of the subject will broaden the range of therapeutic options and improve patient outcomes.

Keywords: molecular medicine; proteasome inhibitors; treatment resistance.

Figure 1

Schematic representation of the ubiquitylation machinery. (A). Three consecutive reactions lead to ubiquitin (Ub) attachment to the target protein. First, the E1 enzyme forms a covalent bond with Ub at the expense of energy from ATP. Then, Ub is transferred from the E1 to the E2 enzyme. Finally, the E3 enzyme catalyzes the transfer of Ub from E2 to the target protein. (B). Basic notions in the ubiquitylation code. A monoubiquitylated protein has a single Ub molecule attached to it. A multimonoubiquitylated protein has several Ub molecules attached at different sites. A polyubiquitylated protein has several Ub molecules attached as a chain at one site of this protein. This figure was created with BioRender.com.

Figure 2

Schematic structure of the constitutive 26S proteasome and its tissue-specific variants. The proteasome comprises the 20S core particle and the 19S regulatory particle at one or both ends of the core particle. The core particle contains four heptameric rings (two inner β rings and two outer α rings) stacked on top of each other. Each inner β ring possesses three catalytic subunits (β1, β2, and β5, all depicted with notches), which cleave the target protein into peptides. The outer α rings gate the way to the interior of the core particle. The 19S regulatory particle is composed of (i) a hexameric ring built of Rpt ATPases (the base) unfolding the target protein and (ii) a multi-subunit complex (the lid) responsible for the recognition of target proteins. Tissue-specific proteasomes contain analogs of selected subunits (green in the figure), altering protein specificity and allowing different peptides to be generated. Immunoproteasomes contain β1i, β2i, and β5i subunits, thymoproteasomes have a β5t subunit, and spermatoproteasomes contain a α4s subunit.

Figure 3

Chemical structures of bortezomib (BTZ), ixazomib (IXZ), and carfilzomib (CFZ). Red ellipses highlight the active groups: boronate in BTZ and IXZ and epoxyketone in CFZ. Blue rectangles indicate peptide bonds, indicating that all three compounds are oligopeptides.

Figure 4

Diagram of potential targets for overcoming resistance to proteasome inhibitors. Bold font denotes targets that have been evaluated in clinical trials. Underlined targets have been approved by the FDA and EMA for treatment in combination with proteasome inhibitors.