title: Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells.
abstract: Purpose:The ubiquitin proteasome pathway is a validated therapeutic target in multiple myeloma. Deubiquitylating enzyme USP1 participates in DNA damage response and cellular differentiation pathways. To date, the role of USP1 in multiple myeloma biology is not defined. In the present study, we investigated the functional significance of USP1 in multiple myeloma using genetic and biochemical approaches.Experimental Design:To investigate the role of USP1 in myeloma, we utilized USP1 inhibitor SJB3-019A (SJB) for studies in myeloma cell lines and patient multiple myeloma cells.Results:USP1-siRNA knockdown decreases multiple myeloma cell viability. USP1 inhibitor SJB selectively blocks USP1 enzymatic activity without blocking other DUBs. SJB also decreases the viability of multiple myeloma cell lines and patient tumor cells, inhibits bone marrow plasmacytoid dendritic cell-induced multiple myeloma cell growth, and overcomes bortezomib resistance. SJB triggers apoptosis in multiple myeloma cells via activation of caspase-3, caspase-8, and caspase-9. Moreover, SJB degrades USP1 and downstream inhibitor of DNA-binding proteins as well as inhibits DNA repair via blockade of Fanconi anemia pathway and homologous recombination. SJB also downregulates multiple myeloma stem cell renewal/survival-associated proteins Notch-1, Notch-2, SOX-4, and SOX-2. Moreover, SJB induced generation of more mature and differentiated plasma cells. Combination of SJB and HDACi ACY-1215, bortezomib, lenalidomide, or pomalidomide triggers synergistic cytotoxicity.Conclusions:Our preclinical studies provide the framework for clinical evaluation of USP1 inhibitors, alone or in combination, as a potential novel multiple myeloma therapy.Clin Cancer Res; 23(15); 4280-9. ©2017 AACR.
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Deepika Sharma
authors.initials: DS
authors.lastname: Das
authors.affiliation: Program in Cellular and Molecular Medicine, Children's Hospital, Boston, Massachusetts.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Das
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Arghya
authors.initials: A
authors.lastname: Ray
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Mehmet Kemal
authors.initials: MK
authors.lastname: Samur
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Dharminder_Chauhan@dfci.harvard.edu Kenneth_Anderson@dfci.harvard.edu.
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Dharminder_Chauhan@dfci.harvard.edu Kenneth_Anderson@dfci.harvard.edu.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D013792:Thalidomide; D000069286:Bortezomib; C579228:USP1 protein, human; D064570:Ubiquitin-Specific Proteases; D000077269:Lenalidomide