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December 8, 2025BloodOpen Access

Synthetic lethal targeting of PSMC2-dependent p97-adapted proteasome complexes that confer chemoresistance in multiple myeloma

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Authors

JDJames J. DriscollEMEhsan MalekWHWei Huang

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Overview

Randomised trial shows drug resistance in multiple myeloma patients may be targeted via synthetic lethality, indicating implications for clinical outcomes.

Key Points

  • The study aims to explore the role of proteasome gene expression in drug resistance among multiple myeloma patients.
  • Compared proteasome gene expression between bortezomib responders and non-responders
  • Analyzed patient data from the APEX trial and CoMMpass dataset
  • Conducted a high throughput screen to identify drugs targeting PSMC2
  • Evaluated the effects of CB-5339 in vitro and in vivo against Btz-refractory tumor cells
  • Increased expression of PSMC2 correlated with poorer overall survival in Btz-treated patients
  • CB-5339 demonstrated synthetic lethality in PSMC2-overexpressing cells
  • Combination treatment of CB-5339 and Btz improved survival in murine models
  • PSMC2 enhances binding with proteasomes, contributing to drug resistance

Cite This Study

Driscoll et al. (2025) studied this question.

synapsesocial.com/papers/69362f694fa91c937236de86https://doi.org/10.1182/blood-2025-2176
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1MDM2 Drives Proteasome Inhibitor Resistance and Represents a TP53-Independent Therapeutic Vulnerability in Multiple Myeloma2026 · 1 citations
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  3. 3PSMD3 orchestrates metabolic reprogramming and immunogenic cell death in multiple myeloma2025
  4. 4Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases2024 · 15 citations
  5. 5Abstract 4554: Novel combination therapy for treating proteasome inhibitor-resistant multiple myeloma2024 · 1 citations