Author/Authors :
Chauhan، نويسنده , , Dharminder and Tian، نويسنده , , Ze and Nicholson، نويسنده , , Benjamin and Kumar، نويسنده , , K.G. Suresh and Zhou، نويسنده , , Bin and Carrasco، نويسنده , , Ruben and McDermott، نويسنده , , Jeffrey L. and Leach، نويسنده , , Craig A. and Fulcinniti، نويسنده , , Mariaterresa and Kodrasov، نويسنده , , Matthew P. and Weinstock، نويسنده , , Joseph and Kingsbury، نويسنده , , William D. and Hideshima، نويسنده , , Teru and Shah، نويسنده , , Parantu K. and Minvielle، نويسنده , , Stephane and Altun، نويسنده , , Mikael and Kessler، نويسنده , , Benedikt M. and Orlowski، نويسنده , , Robert and Richardson، نويسنده , , Paul and Munshi، نويسنده , , Nikhil and Anderson، نويسنده , , Kenneth C.، نويسنده ,
Abstract :
Summary
omib 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.
