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PMID: 22975377 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance.

Cancer cell ·Vol. 22 ·No. 3 ·2012-09-11 ·Pages 345-58

Chauhan D, Tian Z, Nicholson B, Kumar KG, Zhou B, Carrasco R, McDermott JL, Leach CA, Fulcinniti M, Kodrasov MP, Weinstock J, Kingsbury WD, Hideshima T, Shah PK, Minvielle S, Altun M, Kessler BM, Orlowski R, Richardson P, Munshi N, Anderson KC

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.

MeSH Terms
Animals Antineoplastic Agents/pharmacology,therapeutic use Antineoplastic Combined Chemotherapy Protocols/pharmacology,therapeutic use Apoptosis/drug effects Boronic Acids/pharmacology,therapeutic use Bortezomib Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p21/antagonists & inhibitors Dexamethasone/pharmacology,therapeutic use Drug Resistance, Neoplasm/drug effects Drug Therapy, Combination Humans Lenalidomide Mice Mice, SCID Molecular Sequence Data Multiple Myeloma/drug therapy,enzymology,pathology Neovascularization, Pathologic/drug therapy Protease Inhibitors/pharmacology,therapeutic use Proto-Oncogene Proteins c-mdm2/metabolism Pyrazines/pharmacology,therapeutic use Random Allocation Thalidomide/analogs & derivatives,pharmacology,therapeutic use Thiophenes/pharmacology,therapeutic use Ubiquitin Thiolesterase/antagonists & inhibitors,genetics Ubiquitin-Specific Peptidase 7 Xenograft Model Antitumor Assays
Chemicals
Antineoplastic Agents Boronic Acids Cyclin-Dependent Kinase Inhibitor p21 P5091 Protease Inhibitors Pyrazines Thiophenes Thalidomide Bortezomib Dexamethasone MDM2 protein, human Proto-Oncogene Proteins c-mdm2 USP7 protein, human Ubiquitin Thiolesterase Ubiquitin-Specific Peptidase 7 Lenalidomide
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Chauhan Dharminder
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
Tian Ze
Nicholson Benjamin
Kumar K G Suresh
Zhou Bin
Carrasco Ruben
McDermott Jeffrey L
Leach Craig A
Fulcinniti Mariaterresa
Kodrasov Matthew P
Weinstock Joseph
Kingsbury William D
Hideshima Teru
Shah Parantu K
Minvielle Stephane
Altun Mikael
Kessler Benedikt M
Orlowski Robert
Richardson Paul
Munshi Nikhil
Anderson Kenneth C
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2012.08.007
Email
dharminder_chauhan@dfci.harvard.edu
Published
2012-09-11
Pages
345-58
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3478134
Subset
IM
Grants
NCI NIH HHS · R43 CA115205 · United States
NIDDK NIH HHS · R43DK071391 · United States
NCI NIH HHS · P01-CA078378 · United States
NCI NIH HHS · P01 CA078378 · United States
PHS HHS · P50100707 · United States
NCI NIH HHS · R01 CA050947 · United States
Medical Research Council · G0501068 · United Kingdom
NCI NIH HHS · P50 CA100707 · United States
NCI NIH HHS · R43CA115205 · United States
NIDDK NIH HHS · R43 DK071391 · United States
NCI NIH HHS · P01 CA155258 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2012.08.007 PMC Full Text View journal details
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