Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
Skip to main content

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

DOI

10.1016/j.ccr.2012.08.007

Type

Journal article

Journal

Cancer Cell

Publication Date

11/09/2012

Volume

22

Pages

345 - 358

Keywords

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