Department of Biology, National University of Ireland, Maynooth, Ireland.
Department of Hematology, Mater Misericordiae University Hospital, Dublin, Ireland.
Sci Rep. 2021 Jun 18;11(1):12866. doi: 10.1038/s41598-021-90149-y.
With the introduction of novel therapeutic agents, survival in Multiple Myeloma (MM) has increased in recent years. However, drug-resistant clones inevitably arise and lead to disease progression and death. The current International Myeloma Working Group response criteria are broad and make it difficult to clearly designate resistant and responsive patients thereby hampering proteo-genomic analysis for informative biomarkers for sensitivity. In this proof-of-concept study we addressed these challenges by combining an ex-vivo drug sensitivity testing platform with state-of-the-art proteomics analysis. 35 CD138-purified MM samples were taken from patients with newly diagnosed or relapsed MM and exposed to therapeutic agents from five therapeutic drug classes including Bortezomib, Quizinostat, Lenalidomide, Navitoclax and PF-04691502. Comparative proteomic analysis using liquid chromatography-mass spectrometry objectively determined the most and least sensitive patient groups. Using this approach several proteins of biological significance were identified in each drug class. In three of the five classes focal adhesion-related proteins predicted low sensitivity, suggesting that targeting this pathway could modulate cell adhesion mediated drug resistance. Using Receiver Operating Characteristic curve analysis, strong predictive power for the specificity and sensitivity of these potential biomarkers was identified. This approach has the potential to yield predictive theranostic protein panels that can inform therapeutic decision making.
随着新型治疗药物的引入，多发性骨髓瘤（MM）的生存率近年来有所提高。然而，耐药克隆不可避免地出现，导致疾病进展和死亡。目前国际骨髓瘤工作组的反应标准较为宽泛，难以明确区分耐药和敏感患者，从而阻碍了针对敏感性的蛋白质组学分析信息生物标志物的研究。在这项概念验证研究中，我们通过将体外药物敏感性测试平台与最先进的蛋白质组学分析相结合，解决了这些挑战。从新诊断或复发的 MM 患者中采集了 35 个 CD138 纯化的 MM 样本，并将其暴露于来自五个治疗药物类别的治疗药物，包括硼替佐米、喹唑啉酮、来那度胺、纳维托克拉克斯和 PF-04691502。使用液相色谱-质谱联用的比较蛋白质组学分析客观地确定了最敏感和最不敏感的患者群体。使用这种方法，在每种药物类别中都鉴定出了几种具有生物学意义的蛋白质。在五类中的三类中，与粘着斑相关的蛋白质预测敏感性较低，这表明靶向该途径可能会调节细胞粘着介导的药物耐药性。使用接收器操作特征曲线分析，鉴定出这些潜在生物标志物的特异性和敏感性具有很强的预测能力。这种方法有可能产生预测性治疗蛋白质组学面板，为治疗决策提供信息。
