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Ref Type Journal Article
PMID (28270494)
Authors Das DS, Das A, Ray A, Song Y, Samur MK, Munshi NC, Chauhan D, Anderson KC
Title Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 15
Date 2017 Aug 01
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
SJB3-019A USP1 inhibitor 3 SJB3-019A irreversibly inhibits USP1, resulting in decreased USP1 deubiquitinylating activity and downstream DNA repair pathway signaling, and reduced tumor cell viability (PMID: 28270494).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown multiple myeloma not applicable Ricolinostat + SJB3-019A Preclinical - Patient cell culture Actionable In a preclinical study, the combination of SJB3-019A and Ricolinostat (ACY-1215) worked synergistically to induce cytotoxicity in multiple myeloma cell lines and primary multiple myeloma cells in culture (PMID: 28270494). 28270494
Unknown unknown multiple myeloma not applicable Lenalidomide + SJB3-019A Preclinical - Patient cell culture Actionable In a preclinical study, the combination of SJB3-019A and Revlimid (lenalidomide) worked synergistically to induce cytotoxicity in multiple myeloma cell lines and primary multiple myeloma cells in culture (PMID: 28270494). 28270494
Unknown unknown multiple myeloma not applicable SJB3-019A Preclinical - Cell culture Actionable In a preclinical study, treatment with SJB3-019A induced cell-cycle arrest and apoptosis and decreased viability of multiple myeloma cell lines in culture (PMID: 28270494). 28270494
Unknown unknown multiple myeloma not applicable Bortezomib + SJB3-019A Preclinical - Patient cell culture Actionable In a preclinical study, the combination of SJB3-019A and Velcade (bortezomib) worked synergistically to induce cytotoxicity in multiple myeloma cell lines and primary multiple myeloma cells in culture (PMID: 28270494). 28270494
Unknown unknown multiple myeloma not applicable Pomalidomide + SJB3-019A Preclinical - Cell culture Actionable In a preclinical study, the combination of SJB3-019A and Pomalyst (pomalidomide) worked synergistically to induce cytotoxicity in multiple myeloma cell lines and primary multiple myeloma cells in culture (PMID: 28270494). 28270494