TY - JOUR
T1 - A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance
AU - Chauhan, Dharminder
AU - Tian, Ze
AU - Nicholson, Benjamin
AU - Kumar, K. G.Suresh
AU - Zhou, Bin
AU - Carrasco, Ruben
AU - McDermott, Jeffrey L.
AU - Leach, Craig A.
AU - Fulcinniti, Mariaterresa
AU - Kodrasov, Matthew P.
AU - Weinstock, Joseph
AU - Kingsbury, William D.
AU - Hideshima, Teru
AU - Shah, Parantu K.
AU - Minvielle, Stephane
AU - Altun, Mikael
AU - Kessler, Benedikt M.
AU - Orlowski, Robert
AU - Richardson, Paul
AU - Munshi, Nikhil
AU - Anderson, Kenneth C.
N1 - Funding Information:
This investigation was supported by grants from the National Institutes of Health (P50100707, PO1-CA078378, R43DK071391, and R43CA115205). M.A. is supported by VR-2011-2686. K.C.A. is an ACS Clinical Research Professor. D.C. designed research, analyzed data, and wrote the manuscript; Z.T. performed experiments and interpreted data; B.N. designed USP7 activity assay and analyzed data; B.Z. did microscopy; R.C. performed IHC; S.K., C.A.L., J.L.M., M.P.K., M.A., and B.M.K. performed DUB assays; J.W. and W.D.K. synthesized compounds; P.S., S.M., and N.M. analyzed microarray data; M.T. performed animal study; T.H. and P.R. provided clinical samples; and K.C.A. wrote the manuscript. We thank Dr. Bert Vogelstein for HCT116 USP7- and p53-KO cells. We are thankful to Dr. William G. Kaelin (DFCI, Boston, MA) for p53 −/− cells and Dr. Guillermina Lozano (M.D. Anderson Cancer Center, Houston, TX) for p53 −/− /MDM2 −/− cells. B.N., S.K., C.A.L., J.L.M., M.P.K., J.W., and W.D.K. are employees of Progenra, Inc.
PY - 2012/9/11
Y1 - 2012/9/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2012.08.007
DO - 10.1016/j.ccr.2012.08.007
M3 - Article
C2 - 22975377
AN - SCOPUS:84866021069
SN - 1535-6108
VL - 22
SP - 345
EP - 358
JO - Cancer cell
JF - Cancer cell
IS - 3
ER -