Proteasome Assembly Chaperones in Sensitivity and Resistance to Proteasome Inhibitors

 描述(申请人提供)：调节的细胞内蛋白分解通过泛素-蛋白酶体途径发生，蛋白酶体抑制剂(PI)已被我们小组和其他人的研究证实为多发性骨髓瘤的关键治疗药物。在发育过程中，浆细胞的蛋白质周转能力降低，同时它们面临着大量错误折叠的免疫球蛋白，造成了失衡和细胞应激，而PI进一步加剧了这种失衡和细胞压力，这可能解释了它们对这类药物的独特敏感性。然而，在复发/难治的情况下，只有一小部分患者通过单一药物治疗实现完全缓解，而绝大多数患者最终产生耐药性。我们的团队做了一个新的观察，即在PI抗性的背景下，负责新的蛋白酶体组装的伴侣及其相关的信号通路被激活。此外，阻断这些通路既可以在药物幼稚的环境中使PI增敏，又可以在体外和体内克服PI的耐药性。这些发现支持我们的中心假说，即原发和继发的PI抗性是由促进蛋白酶体能力扩大的蛋白酶体组装伴侣介导的，这些伴侣及其相关途径是PI敏感性的合理生物标志物，也是提高PI疗效的潜在靶点。为了评估这些可能性，建议进行更多的研究，以进一步剖析蛋白酶体组装和PI抗性所涉及的分子途径。此外，基因组研究将与Bortezomib和carfilzomib的预期合作小组试验一起进行，以验证我们感兴趣的基因之一MUC20的表达以及HGF/c-MET和p44/42MAPK的相关激活信号可能有助于确定最有可能从基于PI的治疗中受益的患者。最后，抑制这些通路的活性或可能增强MUC20表达的方法将被评估其诱导化疗敏感性的能力，并在细胞系、原代样本和生理相关的活体小鼠模型中克服化疗耐药性。

 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.