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Identifying novel, targetable pathways to restore drug potency is of utmost importance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental approach<\/jats:title>\n                    <jats:p>Insulin\u2010degrading 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\u2010ray 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key results<\/jats:title>\n                    <jats:p>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\u2010Myc and induces integrated stress response and DNA damage. Whilst sparing the tumour micro\u2010environment, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and implications<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70407","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T07:23:00Z","timestamp":1773904980000},"page":"3355-3376","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing antitumour response to proteasome inhibitors with inhibitors of insulin\u2010degrading enzyme, a new molecular vulnerability in multiple myeloma"],"prefix":"10.1111","volume":"183","author":[{"given":"Laetitia","family":"Lesire","sequence":"first","affiliation":[{"name":"U1177\u2010Drugs and Molecules for Living Systems INSERM, Institut Pasteur de Lille, Universit\u00e9 de Lille  Lille 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