文章：

“直接找药”筛查作为多发性骨髓瘤的精准医疗工具

“Direct to Drug” screening as a precision medicine tool in multiple myeloma

原文发布日期：2020-05-11

DOI: 10.1038/s41408-020-0320-7

类型: Article

开放获取: 是

英文摘要：

Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin’s lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This “direct to drug” screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.
 

摘要翻译： 

对76种FDA批准的肿瘤药物及新兴疗法进行了评估，涉及25个多发性骨髓瘤和15个非霍奇金淋巴瘤细胞系，以及113例原发多发性骨髓瘤样本。研究通过离体药物敏感性检测，分析了其与临床表型、细胞遗传学特征、基因突变及转录谱之间的关联。在原发多发性骨髓瘤样本中，蛋白酶体抑制剂、dinaciclib、selinexor、venetoclax、金诺芬以及组蛋白去乙酰化抑制剂展现出最广泛的细胞毒性。值得注意的是，新确诊患者的样本整体敏感性较低，尤其对溴结构域抑制剂、受体酪氨酸激酶或非受体激酶抑制剂以及DNA合成抑制剂的反应更为明显。聚类分析揭示了六种与基因组生物标志物及临床结局相关的药物敏感性特征群。例如，我们的发现复现了t(11;14)患者对venetoclax应答增强的临床观察，同时识别出在未经治疗患者、标准遗传风险群体、低浆细胞S期占比、无Gain(1q)和t(4;14)异常的患者中存在更显著的敏感性特征。相反，对selinexor的离体敏感性升高则与不良预后生物标志物及晚期复发患者相关。这一"直接药敏检测"资源结合功能基因组学，有望为多发性骨髓瘤患者精准指导个体化治疗方案，并为临床试验筛选潜在应答者提供支撑。

原文链接：

“Direct to Drug” screening as a precision medicine tool in multiple myeloma