Kumar S., Paiva B., Anderson K.C., Durie B., Landgren O., Moreau P., Munshi N., Lonial S., Bladé J., Mateos M.-V., et al. Genomic complexity of multiple myeloma and its clinical implications. Manier S., Salem K.Z., Park J., Landau D.A., Getz G., Ghobrial I.M.
The proteasome and proteasome inhibitors in multiple myeloma. Gandolfi S., Laubach J.P., Hideshima T., Chauhan D., Anderson K.C., Richardson P.G. Kumar S.K., Rajkumar V., Kyle R.A., Van Duin M., Sonneveld P., Mateos M.-V., Gay F., Anderson K.C. The EZH1/EZH2 inhibitor UNC1999 enhances the cytotoxicity of PI through a cooperative repression of MYC transcription. It is speculated that DAC inhibits β-catenin activity by promoting the expression of Wnt antagonists (DKK-1 and sFRP3). The DNA hypomethylating agent decitabine (DAC) demonstrated synergistic anti-MM effects in combinations with bortezomib. The BET inhibitor JQ1 in combination with carfilzomib enhances CHOP/EBPα-dependent Bim and Mcl-1 transcription, thus triggering ER stress and apoptosis. Multiple pathways are responsible for the synergy between EDO-S101 and proteasome inhibitors, such as UPR hyper-activation, induction of autophagy, inhibition of cell cycle via upregulation of p21, and reduction of c-MYC expression.
EDO-S101 promotes polyUb-proteins accumulation, p21 expression, and induces DNA damage. The fusion molecule EDO-S101 acts as HDAC inhibitor as well as alkylating agent. MPT0G413 can also affect MM cell growth, survival and adhesion to bone marrow stromal cells(BMSCs), through the inhibition of adhesion molecules and cytokines expression. This mechanism is emphasized by proteasome inhibition. HDAC6 specific inhibitors (MPT0G413, Tubacin, ACY-1215, WT161) lead to increased α-tubulin acetylation and to the inhibition of aggresomal pathways, thus activating unfolded protein response (UPR) and autophagy pathways. A plethora of anti-myeloma effects are observed by targeting epigenetic reprogrammers in combination with proteasome inhibition. The molecular mechanisms underlying the effects of proteasome inhibitors (PIs) combination with epigenetic inhibitors. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.Ĭombinatorial treatment drug resistance multiple myeloma proteasome inhibitors synthetic lethality. 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. 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. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. 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. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment.