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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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SUMOylation inhibition overcomes proteasome inhibitor resistance in multiple myeloma

Guus J J E Heynen1,2, Francis Baumgartner1,3, Michael Heider4

  • 1Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Blood Advances
|August 2, 2022
PubMed

Insights

Proteasome inhibitor resistance in multiple myeloma (MM) can be overcome by targeting the SUMOylation pathway. Combining a SUMO E1 inhibitor with carfilzomib shows promise for treating resistant MM.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Proteasome inhibitors are effective for multiple myeloma (MM) but resistance develops, leading to poor outcomes.
  • Hyperactive small ubiquitin-like modifier (SUMO) signaling is linked to cancer progression and aggressive biology.
  • Relapsed/refractory MM exhibits a SUMO-high state, with high expression of the SUMO E1-activating enzyme (SAE1/UBA2) correlating with poor survival.

Purpose of the Study:

  • To investigate activated SUMOylation as a therapeutic target in MM.
  • To evaluate the efficacy of combining a SUMO E1-activating enzyme inhibitor (subasumstat) with a proteasome inhibitor (carfilzomib) in MM.

Main Methods:

  • Assessed SUMOylation status in relapsed/refractory MM.
  • Treated MM cell lines and primary cells with subasumstat and carfilzomib (CFZ).
  • Evaluated combination therapy in murine MM xenograft models.
  • Investigated mechanisms including genotoxic/proteotoxic stress and apoptosis induction.

Main Results:

  • Relapsed/refractory MM shows high SUMOylation and SAE1/UBA2 expression.
  • Carfilzomib treatment enhances SUMO pathway activity.
  • Subasumstat synergized with CFZ in sensitive and resistant MM cells, regardless of TP53 status.
  • Combination therapy demonstrated efficacy in preclinical models.

Conclusions:

  • Activated SUMOylation is a viable therapeutic target in MM.
  • Combined SUMO and proteasome inhibition offers a novel strategy for treating proteasome inhibitor-resistant MM.

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