Rychak Emily, Mendy Derek, Shi Tao, Ning Yuhong, Leisten Jim, Lu Ling, Miller Karen, Narla Rama K, Orlowski Robert Z, Raymon Heather K, Bjorklund Chad C, Thakurta Anjan, Gandhi Anita K, Cathers Brian E, Chopra Rajesh, Daniel Thomas O, Lopez-Girona Antonia
Celgene Corporation, San Diego, CA, USA.
Celgene Corporation, Summit, NJ, USA.
Br J Haematol. 2016 Mar;172(6):889-901. doi: 10.1111/bjh.13905. Epub 2016 Feb 23.
Pomalidomide is an IMiD(®) immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, ; San Miguel et al, 2013; Richardson et al, 2014; Scott, ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti-proliferative and pro-apoptotic activity in both lenalidomide-sensitive and lenalidomide-resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single-agent treatment in xenografts of lenalidomide-resistant H929 R10-1 cells. Typical hallmarks of IMiD compound activity, including IKZF3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC, seen in lenalidomide-sensitive H929 MM cell lines, were also observed in PomDex-treated lenalidomide-resistant H929 MM cells. Remarkably, this resulted in strong, synergistic effects on the induction of apoptosis in both lenalidomide-sensitive and resistant MM cells. Furthermore, gene expression profiling revealed a unique differential gene expression pattern in PomDex-treated samples, highlighted by the modulation of pro-apoptotic pathways in lenalidomide-resistant cells. These results provide key insights into molecular mechanisms of PomDex in the lenalidomide-resistant setting.
泊马度胺是一种免疫调节药物（IMiD®），无论对来那度胺或硼替佐米是否耐药，当与地塞米松联合使用时，已在复发和/或难治性多发性骨髓瘤（rrMM）患者中显示出显著的临床益处。（谢伊等人，；圣米格尔等人，2013年；理查森等人，2014年；斯科特，）在这项研究中，我们展示了临床前数据，表明泊马度胺与地塞米松联合使用（PomDex）在来那度胺敏感和耐药的骨髓瘤细胞系中均表现出强大的抗增殖和促凋亡活性。与单药治疗相比，PomDex在来那度胺耐药的H929 R10 - 1细胞异种移植模型中也能协同抑制肿瘤生长。在来那度胺敏感的H929骨髓瘤细胞系中观察到的IMiD化合物活性的典型特征，包括IKZF3（艾洛斯）降解以及干扰素调节因子（IRF）4和MYC的下调，在接受PomDex治疗的来那度胺耐药H929骨髓瘤细胞中也被观察到。值得注意的是，这对来那度胺敏感和耐药的骨髓瘤细胞凋亡诱导产生了强烈的协同作用。此外，基因表达谱分析揭示了PomDex处理样本中独特的差异基因表达模式，在来那度胺耐药细胞中促凋亡途径的调节尤为突出。这些结果为PomDex在来那度胺耐药情况下的分子机制提供了关键见解。
