Enhancing antitumour response to proteasome inhibitors with inhibitors of insulin-degrading enzyme, a new molecular vulnerability in multiple myeloma

  • Br J Pharmacol. 2026 Jun;183(12):3355-3376. doi: 10.1111/bph.70407.
Laetitia Lesire  1 ,  Rebecca Deprez-Poulain  2 ,  Damien Bosc  1 ,  Florence Leroux  1 ,  Valerie Landry  1 ,  Sarah Ourabah  3 ,  Morgane Tardy  1 ,  Clara Maillard  1 ,  Ronan Gealageas  1 ,  Julie Dumont  1 ,  Adrien Herledan  1 ,  Sandrine Warenghem  1 ,  Manon Cruette  1 ,  Celine Lenglart  1 ,  Alexandre Biela  1 ,  Catherine Piveteau  1 ,  Eva De Smedt  4 ,  Catharina Muylaert  4 ,  Wenguang Liang  5 ,  Elvira Garcia De Paco  6 ,  Elina Alaterre  7 ,  Sara Ovejero  6  7 ,  Nicolas Robert  6 ,  Fabien Delahaye  8 ,  Wei-Jen Tang  5 ,  Peter van Endert  3 ,  Elke De Bruyne  4 ,  Jérôme Moreaux  6  7  9  10 ,  Benoit Deprez  2
Affiliations
  • 1. U1177-Drugs and Molecules for Living Systems, INSERM, Institut Pasteur de Lille, Université de Lille, Lille, France.
  • 2. U1177-EGID-Drugs and Molecules for Living Systems, INSERM, Institut Pasteur de Lille, Université de Lille, Lille, France.
  • 3. Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, INSERM, CNRS, Institut Necker Enfants Malades, Université Paris Cité, Paris, France.
  • 4. Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
  • 5. Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA.
  • 6. Department of Biological Hematology, CHU Montpellier, Montpellier, France.
  • 7. Institute of Human Genetics, Unité Mixte de Recherche, Centre National de la Recherche Scientifique, Université Montpellier, Montpellier, France.
  • 8. Institut Pasteur de Lille, U1283-UMR 8199 EGID, Université de Lille, Inserm, CNRS, CHU Lille, Lille, France.
  • 9. UFR Medicine, University of Montpellier, Montpellier, France.
  • 10. Institut Universitaire de France, Paris, France.
PMID: 41852107 DOI: 10.1111/bph.70407
Abstract

Background and purpose: Multiple myeloma (MM) patients frequently develop resistance to Proteasome inhibitors (PIs). Identifying novel, targetable pathways to restore drug potency is of utmost importance.

Experimental approach: Insulin-degrading enzyme (IDE) regulates the activity of the Proteasome. We hypothesised that targeting IDE could boost MM response to PIs. We have interrogated the transcriptomic data of a cohort of MM patients and developed novel IDE inhibitors. X-ray crystallography, enzymatic assays and engagement studies showed that these inhibitors bind IDE with high affinity. We treated MM cell lines, and primary MM cells from newly diagnosed or relapsing patients, with IDE inhibitors and PIs to measure their synergy in inducing Apoptosis. We used transcriptomic analysis to describe the underlying molecular mechanism. We confirmed these results in a mouse model of MM.

Key results: Low expression of IDE is associated with a higher overall survival in MM patients. When MM cells are treated with IDE inhibitors at a concentration that fully engages IDE, the chymotrypsin activity of the Proteasome is more sensitive to PI. Their combination reduces c-Myc and induces integrated stress response and DNA damage. Whilst sparing the tumour micro-environment, they enhanced the cytotoxicity of PI in resistant MM cell lines and cells from relapsing patients. Finally, an optimised IDE Inhibitor boosts bortezomib in a syngeneic, immunocompetent MM mouse model.

Conclusions and implications: IDE emerges as a novel biomarker and therapeutic vulnerability in MM. This study demonstrates the relevance of IDE inhibitors as boosters of PIs to better treat patients with resistant MM.

Keywords
IDE inhibitors; carfilzomib; drug resistance; insulin‐degrading enzyme; integrated stress response; multiple myeloma; proteasome inhibitors; synergy.
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