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Published on: May 15, 2019
Modulating proteasome inhibitor tolerance in multiple myeloma: an alternative strategy to reverse inevitable
Maolin Ge1, Zhi Qiao2, Yan Kong3
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. mge@whu.edu.cn.
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.
Insights
Proteasome inhibitor resistance in multiple myeloma is reversible and linked to epigenetic changes. Combination therapies targeting epigenetic regulators can prevent resistance and improve treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Proteasome inhibitors (PIs) are crucial for multiple myeloma (MM) treatment.
- Acquired resistance to PIs remains a significant clinical challenge.
- Mechanisms of PI resistance and its reversal in MM are not fully understood.
Purpose of the Study:
- To investigate the mechanisms of acquired and reversible resistance to proteasome inhibitors in multiple myeloma.
- To identify strategies for overcoming PI resistance through epigenetic modulation.
Main Methods:
- Utilized MM patient relapse samples, cell lines, and mouse models to generate resistant and reversed cells.
- Employed RNA sequencing and bioinformatics to analyze epigenetic regulators.
- Conducted in vitro and in vivo experiments to characterize drug-tolerant cells and assess therapeutic efficacy.
Main Results:
- Multiple myeloma cells develop a reversible, slow-cycling, drug-tolerant state upon PI treatment, linked to epigenetic plasticity.
- This tolerance, rather than true persistence, characterizes relapsed MM.
- Combination therapy with histone deacetylase inhibitors and intermittent high-dose PI showed improved efficacy by preventing PI-tolerant cell emergence.
Conclusions:
- Proposed a non-mutational mechanism for PI resistance and sensitivity reversal after drug holidays.
- Highlighted the role of epigenetic plasticity in PI resistance.
- Suggested combination therapies targeting epigenetic regulators as a strategy to eliminate drug-tolerant MM cells.
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