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.
Cancer Cell. 2012 Sep 11;22(3):345-58. doi: 10.1016/j.ccr.2012.08.007.
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.
硼替佐米疗法已被证明对治疗复发/难治性、复发性和新诊断的多发性骨髓瘤（MM）有效；然而，剂量限制毒性和耐药性的发展限制了其长期应用。在这里，我们表明 P5091 是去泛素化酶 USP7 的抑制剂，它诱导对常规和硼替佐米治疗耐药的 MM 细胞凋亡。生化和遗传研究表明，阻断 HDM2 和 p21 可消除 P5091 诱导的细胞毒性。在动物肿瘤模型研究中，P5091 具有良好的耐受性，能抑制肿瘤生长，延长生存期。将 P5091 与来那度胺、HDAC 抑制剂 SAHA 或地塞米松联合使用可引发协同抗 MM 活性。因此，我们的临床前研究支持对 USP7 抑制剂进行临床评估，无论是单独使用还是联合使用，作为一种潜在的 MM 治疗方法。
