Proteasome Assembly Chaperones in Sensitivity and Resistance to Proteasome Inhibitors

 描述（由申请人提供）：通过泛素-蛋白酶体途径发生调节性细胞内蛋白水解，我们小组和其他人的研究已证实蛋白酶体抑制剂（PI）是多发性骨髓瘤的关键治疗药物。浆细胞的蛋白质周转能力在其发育过程中降低，同时它们面临着高负荷的错误折叠的免疫球蛋白，从而产生不平衡和细胞应激，PI进一步加剧了这种不平衡和细胞应激，这可能解释了它们对这类药物的独特敏感性。然而，只有少数复发/难治性患者在单药治疗后达到完全缓解，而绝大多数患者最终会产生耐药性。我们的小组已经作出了新的观察，伴侣负责新的蛋白酶体组装，及其相关的信号通路，在PI抗性的设置被激活。此外，这些途径的中断可以在药物初治环境中对PI增敏，并在体外和体内克服PI耐药性。这些研究结果支持我们的中心假设，提出原发性和继发性PI抗性是由蛋白酶体组装分子伴侣介导的，其促进蛋白酶体能力的细胞扩增，并且这些分子伴侣及其相关途径是PI敏感性的合理生物标志物，以及用于增强PI功效的方法的潜在靶点。为了评估这些可能性，提出了额外的研究，以进一步剖析参与蛋白酶体组装和PI抗性的分子途径。此外，基因组研究将与硼替佐米和卡非佐米的前瞻性合作组试验联合进行，以验证我们感兴趣的基因之一MUC 20的表达以及HGF/c-MET和p44/42 MAPK的相关激活特征可能有助于识别最有可能从基于PI的治疗中获益的患者。最后，将评价抑制这些途径的活性或可能增强MUC 20表达的方法在细胞系、原代样品和生理学相关的体内鼠模型中诱导化学增敏和克服化学抗性的能力。

 DESCRIPTION (provided by applicant): Regulated intracellular proteolysis occurs through the ubiquitin-proteasome pathway, and proteasome inhibitors (PIs) have been validated as key therapeutic agents in multiple myeloma by studies from our group and others. Plasma cell capacity for protein turnover is reduced during their development, while they are at the same time faced with a high load of misfolded immunoglobulins, creating an imbalance and cellular stress which are further exacerbated by PIs, which may explain their unique sensitivity to this class of drugs. However, only a minority of patients in the relapsed/refractory setting achieve complete remissions with single agent therapy, while the vast majority eventually develop drug resistance. Our group has made the novel observation that chaperones responsible for new proteasome assembly, and their associated signaling pathways, are activated in the setting of PI resistance. Moreover, interruption of these pathways can both sensitize to PIs in the drug-naïve setting, and overcome PI resistance in vitro and in vivo. These findings support our central hypothesis, which proposes that primary and secondary PI resistance is mediated by proteasome assembly chaperones which promote cellular expansion of proteasome capacity, and that these chaperones and their associated pathways are rational biomarkers of PI sensitivity, as well as potential targets for approaches to enhance the efficacy of PIs. To evaluate these possibilities, additional studies are proposed to further dissect the molecular pathways involved in proteasome assembly and PI resistance. In addition, genomic studies will be performed in association with prospective cooperative group trials of bortezomib and carfilzomib to validate the possibility that expression of one of our genes of interest, MUC20, and associated activation signatures of HGF/c-MET and p44/42 MAPK, may help to identify patients who are most likely to benefit from PI-based therapy. Finally, approaches to suppress the activity of these pathways, or possibly of enhancing MUC20 expression, will be evaluated for their ability to induce chemosensitization, and overcome chemoresistance in cell lines, primary samples, and physiologically relevant in vivo murine models.