Gene expression profile of multiple myeloma cell lines treated with CB-5083

The goal was to determine the gene expression differences between CB-5083 and Bortezomib treated multiple myeloma cell lines Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system (UPS) and CB-5083, a first in class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematological and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma (MM) cell lines and a number of in vivo MM models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response (UPR) and apoptosis. CB-5083 decreases viability in MM cell lines and patient derived MM cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant MM models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with MM standard of care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several MM disease models and provide the rationale for clinical evaluation as monotherapy and in combination in MM. Cells were treated with compound or DMSO for 8hrs and then processed for RNAseq

本研究旨在探究经CB-5083与硼替佐米（Bortezomib）处理的多发性骨髓瘤细胞系之间的基因表达差异。近期研究显示，抑制AAA ATP酶p97是靶向泛素-蛋白酶体系统（ubiquitin proteasome system, UPS）的全新策略；而CB-5083作为首款p97抑制剂，已在多种血液系统及实体瘤模型中展现出广谱抗肿瘤活性。本研究证实，CB-5083对多发性骨髓瘤（MM）细胞系及多种体内MM模型均具有强效活性。CB-5083处理可引发泛素化蛋白积累、未折叠蛋白反应（unfolded protein response, UPR）激活以及细胞凋亡。CB-5083可降低MM细胞系及患者来源MM细胞的存活率，其中包括携带蛋白酶体抑制剂（proteasome inhibitor, PI）耐药背景的细胞。CB-5083具有独特的作用机制，可与PI类药物产生良好协同效应，这一现象可能源于p97依赖的转录因子Nrf1的逆向转位：当细胞暴露于PI后，Nrf1可转录蛋白酶体亚基基因。采用临床相关MM模型开展的体内研究证实，单药CB-5083可抑制肿瘤生长，且与MM标准治疗药物具有良好的协同效果。本研究的临床前数据证实了CB-5083在多种MM疾病模型中的疗效，并为其作为单药及联合疗法在MM中的临床评估提供了理论依据。将细胞用受试化合物或二甲基亚砜（DMSO）处理8小时后，进行RNAseq样本处理。