Abstract
Multiple myeloma (MM) is a plasma cell disorder typically characterized by abundant synthesis of clonal immunoglobulin or free light chains. Although incurable, a deeper understanding of MM pathobiology has fueled major therapeutical advances over the past two decades, significantly improving patient outcomes. Proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies are among the most effective anti-MM drugs, targeting not only the cancerous cells, but also the bone marrow microenvironment. However, de novo resistance has been reported, and acquired resistance is inevitable for most patients over time, leading to relapsed/refractory disease and poor outcomes. Sustained protein synthesis coupled with impaired/insufficient proteolytic mechanisms makes MM cells exquisitely sensitive to perturbations in protein homeostasis, offering us the opportunity to target this intrinsic vulnerability for therapeutic purposes. This review highlights the scientific rationale for the clinical use of FDA-approved and investigational agents targeting protein homeostasis in MM.
Highlights
Potential molecular targets within the ubiquitin-proteasome system (UPS) include enzymes involved in ubiquitination (E1, E2, E3) and deubiquitination (DUBs) of proteins destined for proteasomal degradation[55,56]
Similar to proteasome inhibitor (PI), deubiquitinating enzymes (DUBs) inhibitors induce apoptosis in preclinical MM models preceded by accumulation of polyubiquitinated proteins and in a manner that is independent from the inhibition of the proteasome catalytic activity[57]
A pathognomonic hallmark of MM is the intense synthesis of Ig, coupled with insufficient proteolytic mechanisms, resulting in pervasive, baseline proteotoxic stress
Summary
Multiple myeloma (MM) is a clonal proliferation of malignant plasma cells, the product of the terminal www.cdrjournal.com. Increasing protein misfolding via ER stressors results in increased sensitivity to PI, while augmenting proteasome activity or inducing alternative proteolytic pathways mediates PI resistance[14]. Recent preclinical studies show potent activity of marizomib even in bortezomib-resistant MM cells, suggesting that broader blockade of proteasome subunits may increase effectiveness[53,54].
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