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

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

  • Cancer Cell. 2012 Sep 11;22(3):345-58. doi: 10.1016/j.ccr.2012.08.007.
Dharminder Chauhan 1,  Ze Tian,  Benjamin Nicholson,  K G Suresh Kumar,  Bin Zhou,  Ruben Carrasco,  Jeffrey L McDermott,  Craig A Leach,  Mariaterresa Fulcinniti,  Matthew P Kodrasov,  Joseph Weinstock,  William D Kingsbury,  Teru Hideshima,  Parantu K Shah,  Stephane Minvielle,  Mikael Altun,  Benedikt M Kessler,  Robert Orlowski,  Paul Richardson,  Nikhil Munshi,  Kenneth C Anderson
Affiliations

Affiliation

  • 1 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
PMID: 22975377 DOI: 10.1016/j.ccr.2012.08.007
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.

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