The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Abstract

Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.

Metabolic Disorders in Multiple Myeloma

“…Interestingly, anti-mitochondrial agents have shown to restore the sensitivity of myeloma cells to proteasome inhibitors [ 39 ]. The combination of metabolic regulators with proteasome inhibitors may induce synthetic lethality, prevent the activation of resistance mechanisms and increase efficacy [ 141 , 149 ]. Recently, preclinical studies have shown that adaptive natural killer cells have decreased CD38 expression and enhanced metabolic fitness by resisting oxidative stress, which may lead to improved anti-myeloma activity in the relapsed disease setting [ 150 , 151 ].…”

Mitochondrial Determinants of Anti-Cancer Drug-Induced Cardiotoxicity

“…To overcome the cardiotoxicity of PIs like carfilzomib, mitochondrial functions affected by PIs are being dissected, and novel PIs devoid of cardiotoxicity are also being developed and analyzed in preclinical studies [222]. Combination strategies reducing PI doses are currently being evaluated in clinical trials to counteract dose-dependent CVAEs [223].…”

Genome Instability in Multiple Myeloma: Facts and Factors

“…This problem becomes even more important nowadays because new drugs for MM treatment appear every year. Some of these drugs are based on new principles of action (e.g., monoclonal antibodies, CAR T-cell therapy, targeted delivery of chemotherapeutic drugs, such as melphalan flufenamide or antibody–drug conjugates), while others are developed on a platform of new knowledge about the genetic plasticity of the MM genome (e.g., histone deacetylase inhibitors, drugs targeting DNA or histone’s methylation pathways, pyrimidine nucleoside analogs) [ 103 , 130 , 132 , 719 , 720 , 721 ]. Next-generation IMiDs, PIs, agents that target the ubiquitin proteasomal cascade, and signaling pathways, are being developed to overcome the limitations of existing therapies [ 719 , 722 , 723 ].…”