title: A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance.
abstract: 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.
authors.affiliation: Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. dharminder_chauhan@dfci.harvard.edu
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Ze
authors.initials: Z
authors.lastname: Tian
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nicholson
authors.forename: K G Suresh
authors.initials: KG
authors.lastname: Kumar
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Ruben
authors.initials: R
authors.lastname: Carrasco
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: McDermott
authors.forename: Craig A
authors.initials: CA
authors.lastname: Leach
authors.forename: Mariaterresa
authors.initials: M
authors.lastname: Fulcinniti
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Kodrasov
authors.forename: Joseph
authors.initials: J
authors.lastname: Weinstock
authors.forename: William D
authors.initials: WD
authors.lastname: Kingsbury
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Parantu K
authors.initials: PK
authors.lastname: Shah
authors.forename: Stephane
authors.initials: S
authors.lastname: Minvielle
authors.forename: Mikael
authors.initials: M
authors.lastname: Altun
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.forename: Robert
authors.initials: R
authors.lastname: Orlowski
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004359:Drug Therapy, Combination; D006801:Humans; D000077269:Lenalidomide; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000076084:Ubiquitin-Specific Peptidase 7; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D050759:Cyclin-Dependent Kinase Inhibitor p21; C576408:P5091; D011480:Protease Inhibitors; D011719:Pyrazines; D013876:Thiophenes; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D000077269:Lenalidomide