Modulating proteasome inhibitor tolerance in multiple myeloma: an alternative strategy to reverse inevitable resistance

Abstract

Background Resistance to proteasome inhibitors (PIs) is a major obstacle to the successful treatment of multiple myeloma (MM). Many mechanisms have been proposed for PI resistance; however, our mechanistic understanding of how PI resistance is inevitably acquired and reversed remains incomplete. Methods MM patients after bortezomib relapse, MM cell lines and mouse models were used to generate matched resistant and reversed cells. RNA sequencing and bioinformatics analyses were employed to assess dysregulated epigenetic regulators. In vitro and in vivo procedures were used to characterise PI-tolerant cells and therapeutic efficacy. Results Upon PI treatment, MM cells enter a slow-cycling and reversible drug-tolerant state. This reversible phenotype is associated with epigenetic plasticity, which involves tolerance rather than persistence in patients with relapsed MM. Combination treatment with histone deacetylase inhibitors and high-dosage intermittent therapy, as opposed to sustained PI monotherapy, can be more effective in treating MM by preventing the emergence of PI-tolerant cells. The therapeutic basis is the reversal of dysregulated epigenetic regulators in MM patients. Conclusions We propose an alternative non-mutational PI resistance mechanism that explains why PI relapse is inevitable and why patients regain sensitivity after a ‘drug holiday’. Our study also suggests strategies for epigenetic elimination of drug-tolerant cells.

Proteomic Assessment of Extracellular Vesicles from Canine Tissue Explants as a Pipeline to Identify Molecular Targets in Osteosarcoma: PSMD14/Rpn11 as a Proof of Principle

“…NF-κB has been demonstrated to be important for OS metastasis [ 62 ], and its activity is regulated by inhibitory kappa B (IκB). IκB bound to NF-kB prevents its nuclear translocation and downstream transcription of target genes [ 63 ]. IκB is a target of the proteasome, and proteasome inhibition may prevent its degradation and thus modulate NF-κB [ 64 ].…”

Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment

“…Even those who express an initial response inevitably develop resistance over time [ 87 ]. Initial studies have established genetic mutations in PSMB5 (encoding proteasome subunit β5) as the underlying cause of PI resistance in vitro [ 157 ]. However, increasing evidence emphasizes the contribution of non-mutational epigenetic mechanisms.…”

Correlation of anti-tumour drug resistance with epigenetic regulation

“…1). Ge et al 4 examined the effects of PI-based intermittent therapy or treatment in combination with histone deacetylase (HDAC) inhibitors on drug-tolerant MM cells, and demonstrated that the combination of HDAC inhibitors and high-dosage intermittent therapies, as opposed to sustained PI monotherapy, can be more effective in treating MM by preventing the emergence of PI-tolerant cells (Fig. 1).…”