Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer.
Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer.
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DOI：
10.1158/0008-5472.can-16-1901
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发表时间：
2017-01-15
期刊：
影响因子：
11.2
通讯作者：
Hatzis C
中科院分区：
文献类型：
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作者：
Wali VB;Langdon CG;Held MA;Platt JT;Patwardhan GA;Safonov A;Aktas B;Pusztai L;Stern DF;Hatzis C
三阴性乳腺癌（TNBC）仍然是一种侵袭性疾病，没有有效的靶向治疗。在这项研究中，我们通过在TNBC细胞系中测试128种FDA批准或研究药物作为单一药物或768种成对药物组合来解决这一挑战，以确定易于临床转化的协同组合。对中通量结果进行了仔细检查，并广泛分析了低通量实验中的敏感性模式、协同作用、抗癌活性和验证。主成分分析显示，一个特定的靶向通路的所有上调或下调的基因的一部分可以部分解释细胞对靶向该通路的药物的敏感性。被认为立即易于转化的联合治疗包括ABT-263/克唑替尼、ABT-263/紫杉醇、紫杉醇/JQ 1、ABT-263/XL 184和紫杉醇/nutlin-3，所有这些在多种TNBC背景中均表现出协同抗增殖和凋亡活性。对ABT-263/克唑替尼联合给药提供了潜在的快速临床途径的机制研究表明，在基底和间充质干细胞样TNBC中，RTK阻断、促有丝分裂信号传导抑制和促凋亡信号诱导。我们的研究结果为TNBC的几种组合治疗提供了临床前概念证明，这些组合治疗为临床转化提供了近期前景。
Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity and validation in low-throughput experiments. Principal component analysis revealed that a fraction of all upregulated or downregulated genes of a particular targeted pathway could partly explain cell sensitivity towards agents targeting that pathway. Combination therapies deemed immediately tractable to translation included ABT-263/crizotinib, ABT-263/paclitaxel, paclitaxel/JQ1, ABT-263/XL184 and paclitaxel/nutlin-3, all of which exhibited synergistic antiproliferative and apoptotic activity in multiple TNBC backgrounds. Mechanistic investigations of the ABT-263/crizotinib combination offering a potentially rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling and pro-apoptotic signal induction in basal and mesenchymal stem-like TNBC. Our findings provide preclinical proof of concept for several combination treatments of TNBC which offer near-term prospects for clinical translation.