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Bortezomib therapy has proven successful for the treatment of relapsed/refractory, relapsed, and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance limit its long-term utility. Here, we show that P5091 is an inhibitor of deubiquitylating enzyme USP7, which induces apoptosis in MM cells resistant to conventional and bortezomib therapies. Biochemical and genetic studies show that blockade of HDM2 and p21 abrogates P5091-induced cytotoxicity. In animal tumor model studies, P5091 is well tolerated, inhibits tumor growth, and prolongs survival. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity. Our preclinical study therefore supports clinical evaluation of USP7 inhibitor, alone or in combination, as a potential MM therapy.

Original publication




Journal article


Cancer Cell

Publication Date





345 - 358


Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Boronic Acids, Bortezomib, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Dexamethasone, Drug Resistance, Neoplasm, Drug Therapy, Combination, Humans, Mice, Mice, SCID, Molecular Sequence Data, Multiple Myeloma, Neovascularization, Pathologic, Protease Inhibitors, Proto-Oncogene Proteins c-mdm2, Pyrazines, Random Allocation, Thalidomide, Thiophenes, Ubiquitin Thiolesterase, Ubiquitin-Specific Peptidase 7, Xenograft Model Antitumor Assays