Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance

Abstract

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity—a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.

Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment

“…Over the last decade therapeutic advances ( 4 ), including the proteasome inhibitor Bortezomib (BTZ, VELCADE®) ( 1 , 5 ), led to improvement in overall MM survival ( 1 ). BTZ targets mainly the β5(i)/β1(i) subunits of the 26S proteosome ( 6 ), resulting in a cascade of events that include the unfolded protein response (UPR) and amino acid deprivation, ultimately leading to cell death ( 7 – 9 ). However, MM remains an incurable disease, with only 57.9% of MM patients reaching 5 years survival (2012–2018) ( 3 ) and ultimately most MM patients relapse after BTZ treatment ( 10 , 11 ).…”

“…MM cells can develop drug resistance via multifactorial mechanisms ( 4 , 8 ). In case of BTZ resistance, adaptation mechanisms include alterations at the level of the proteosome (mutations in the proteosome binding pocket, reduction of the 19S proteosome subunit, up-regulation of proteasomal machinery), upregulation of heat-shock proteins, genetic changes, activation of the aggresome-autophagy pathway, interactions within the MM tumor microenvironment (TME) and metabolic alterations ( 6 , 8 , 12 , 13 ).…”

Novel Class of Proteasome Inhibitors: In Silico and In Vitro Evaluation of Diverse Chloro(trifluoromethyl)aziridines

“…In this regard, the ubiquitin-proteasome pathway (UPP) constitutes the major proteolytic system in the cytosol and nucleus of all eukaryotic cells. It is crucial for maintaining intracellular protein homeostasis in physiological conditions and during adaptive stress responses [ 1 , 2 , 3 , 4 , 5 ]. UPP catalyzes the degradation of most short-lived and long-lived proteins, which comprehend the number of proteins in mammalian cells [ 6 , 7 ].…”

“…On the contrary, the inhibition of all proteasome subunits may develop cytotoxicity [ 28 ]. The majority of 20S PIs currently reported in literature [ 2 , 29 , 30 , 31 ], are peptide-based compounds, featured with a C -terminal electrophilic warhead that forms covalent adducts with the hydroxyl group of Thr1 in the active sites. A reversible mechanism of action is observed for aldehydes ( 1 ) [ 3 , 32 , 33 , 34 ], boronates ( 2–3 ) [ 23 , 24 , 35 , 36 , 37 ], α-keto-amides ( 4 ) [ 37 , 38 ], and α-keto-aldehydes ( 5 ) [ 39 ].…”

“…A reversible mechanism of action is observed for aldehydes ( 1 ) [ 3 , 32 , 33 , 34 ], boronates ( 2–3 ) [ 23 , 24 , 35 , 36 , 37 ], α-keto-amides ( 4 ) [ 37 , 38 ], and α-keto-aldehydes ( 5 ) [ 39 ]. α’,β’-Epoxyketones ( 6 ) [ 3 , 34 , 40 ], β-lactones ( 7 ) [ 41 , 42 ], vinyl sulfones ( 8 ) [ 43 , 44 , 45 ], vinyl esters ( 9 ) [ 46 ], and syrabactins ( 10 ) [ 47 ] act as irreversible inhibitors ( Figure 1 a) [ 2 ]. For the latter, the covalent mode of action and the elevated reactivity of the compounds may often lead to off-target interactions.…”