Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia
Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia
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DOI：
10.1182/blood-2016-09-738070
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发表时间：
2017-03-16
期刊：
影响因子：
20.3
通讯作者：
Bourquin, Jean-Pierre
中科院分区：
文献类型：
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作者：
Frismantas, Viktoras;Dobay, Maria Pamela;Bourquin, Jean-Pierre
对诊断性白血病样本进行药物敏感性和耐药性检测应能提供重要的功能信息，以指导可作用靶点和生物标志物的发现。我们通过对68例急性淋巴细胞白血病（ALL）样本（主要来自骨髓基质细胞共培养中的耐药疾病）中的60种药物进行分析，提供了概念验证数据。患者来源的异种移植物保留了在匹配的患者材料中发现的原始突变模式。基质共培养并未阻止白血病细胞周期活动，但对细胞周期相关药物的特定敏感性特征识别出在体外和作为白血病异种移植物在体内都具有较高细胞增殖的样本。在难治性复发患者中，检测到明显的耐药和对具有直接临床相关性的新药的特殊反应的个体模式。BCL2抑制剂维奈克拉在B细胞前体ALL（BCP - ALL）亚群（包括MLL - AF4和TCF3 - HLF ALL）以及一些T细胞ALL（T - ALL）中，在低于10 nM时具有高度活性，预测其作为单药以及与地塞米松和长春新碱联合使用时在体内的活性。在2个独立的T - ALL队列中检测到对达沙替尼的意外敏感性，其半数最大抑制浓度值低于20 nM，这与SRC抑制剂KX2 - 391的相似细胞毒活性以及对SRC磷酸化的抑制相关。一名难治性T - ALL患者根据药物分析信息接受达沙替尼治疗，并实现了5个月的缓解。因此，药物分析捕捉到了与疾病相关的特征以及对相关药物的意外敏感性，这为在临床试验背景下进一步探索这种功能检测以针对有紧急医疗需求的患者制定药物再利用策略提供了依据。
Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.