Blood Disease Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
J Leukoc Biol. 2018 Dec;104(6):1105-1115. doi: 10.1002/JLB.2A1017-420RR. Epub 2018 Jul 19.
The treatment of multiple myeloma (MM) with bortezomib (BTZ) is promising; however, the emergence of resistance is challenging in the clinical treatment. Thus, a novel targeted treatment or exploring the mechanism underlying BTZ resistance is an urgent requisite. The current data showed that high expression of USP7 in myeloma was a predictor of short overall survival and poor outcome. USP7 knockout significantly suppressed the colony formation, inhibited the proliferation of BTZ-resistant MM cells even in the presence of growth factors, and overcame BTZ resistance. The knockout markedly inhibited the tumor growth and prolonged the survival of mice bearing BTZ-resistant MM cells. Mechanistically, USP7 knockout remarkably increased the sensitivity to BTZ by stabilizing ΙκΒα and blocking the NF-κB pathway. Not surprisingly, when IκBα was knocked down by siRNA transfection, the MM cells restored the BTZ resistance. Importantly, usage of USP7 inhibitors also suppressed the activation of NF-κB and combination with BTZ triggered the synergistic antitumor activity in BTZ-resistant MM cells. Taken together, this study provides the rationale for clinical protocols evaluating USP7 inhibition, alone and in combination with BTZ, to overcome BTZ resistance and improve the patient outcome in MM.
硼替佐米（BTZ）治疗多发性骨髓瘤（MM）有一定前景，但是临床治疗中耐药的出现是一个挑战。因此，迫切需要探索新的靶向治疗或 BTZ 耐药的机制。目前的数据表明，骨髓瘤中 USP7 的高表达是总生存期短和预后不良的预测因子。USP7 敲除显著抑制集落形成，即使在生长因子存在的情况下也能抑制 BTZ 耐药 MM 细胞的增殖，并克服 BTZ 耐药性。敲除明显抑制携带 BTZ 耐药 MM 细胞的小鼠肿瘤生长并延长其存活时间。从机制上讲，USP7 敲除通过稳定 ΙκΒα 和阻断 NF-κB 通路显著增加了对 BTZ 的敏感性。毫不奇怪，当用 siRNA 转染敲低 IκBα 时，MM 细胞恢复了对 BTZ 的耐药性。重要的是，USP7 抑制剂的使用也抑制了 NF-κB 的激活，并且与 BTZ 联合使用在 BTZ 耐药 MM 细胞中引发了协同的抗肿瘤活性。综上所述，这项研究为临床方案提供了依据，评估了 USP7 抑制剂单独使用和与 BTZ 联合使用，以克服 BTZ 耐药性并改善 MM 患者的预后。
