Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma.
Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma.
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DOI：
10.1158/1078-0432.ccr-16-1114
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发表时间：
2017-06-01
期刊：
影响因子：
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通讯作者：
Mossé YP
中科院分区：
文献类型：
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作者：
Wood AC;Krytska K;Ryles HT;Infarinato NR;Sano R;Hansel TD;Hart LS;King FJ;Smith TR;Ainscow E;Grandinetti KB;Tuntland T;Kim S;Caponigro G;He YQ;Krupa S;Li N;Harris JL;Mossé YP
间变性淋巴瘤激酶（ALK）是儿童神经母细胞瘤中最常见的突变癌基因。我们对靶向ALK突变的神经母细胞瘤的协同药物组合进行了体外筛选，以确定药物组合是否可以增强抗肿瘤疗效。我们筛选了8种分子靶向药物的组合，以对抗17种具有全面特征的人神经母细胞瘤衍生细胞系。我们研究了Ceritinib和Ribociclib联合用药对具有代表性ALK状态的细胞系的体外增殖、细胞周期、活力、半胱天冬酶活化以及细胞周期蛋白D/CDK 4/CDK 6/RB和pALK信号网络的影响。我们在携带传统和患者来源异种移植物模型的CB 17 SCID小鼠中进行了体内试验，比较了Ceritinib单药、Ribociclib单药和联合用药，并进行了血浆药代动力学评价，以评估药物间相互作用。Ribociclib（一种细胞周期蛋白依赖性激酶（CDK）4和6的双重抑制剂）与ALK抑制剂Ceritinib联合使用，在ALK突变细胞系中的细胞毒性（p=0.008）和协同作用评分（p=0.006）高于ALK突变或改变缺失的细胞系。与单独使用药物相比，联合治疗增强了生长抑制、细胞周期阻滞和半胱天冬酶非依赖性细胞死亡。联合治疗在具有ALK-F1174 L和F1245 C新发耐药突变的神经母细胞瘤异种移植物中实现了完全消退，并防止了耐药的出现。联合治疗未改变小鼠Ribociclib和Ceritinib的血浆浓度。该临床前联合药物筛选和体内验证为Ceritinib和Ribociclib联合用药在分子选择的儿科人群中的首次儿童试验提供了依据。
Anaplastic Lymphoma Kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an in vitro screen for synergistic drug combinations that target neuroblastomas with mutations in ALK to determine if drug combinations could enhance anti-tumor efficacy. We screened combinations of eight molecularly targeted agents against seventeen comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of Ceritinib and Ribociclib on in vitro proliferation, cell cycle, viability, caspase activation, and the Cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status. We performed in vivo trials in CB17 SCID mice bearing conventional and patient-derived xenograft models comparing Ceritinib alone, Ribociclib alone, and the combination, with plasma pharmacokinetics to evaluate for drug-drug interactions. The combination of Ribociclib, a dual inhibitor of cyclin-dependent kinase (CDK) 4 and 6, and the ALK inhibitor Ceritinib demonstrated higher cytotoxicity (p=0.008) and synergy scores (p=0.006) in cell lines with ALK mutations as compared to cell lines lacking mutations or alterations in ALK. Compared to either drug alone, combination therapy enhanced growth inhibition, cell cycle arrest, and caspase-independent cell death. Combination therapy achieved complete regressions in neuroblastoma xenografts with ALK-F1174L and F1245C de novo resistance mutations, and prevented the emergence of resistance. Murine Ribociclib and Ceritinib plasma concentrations were unaltered by combination therapy. This preclinical combination drug screen with in vivo validation has provided the rationale for a first in children trial of combination Ceritinib and Ribociclib in a molecularly selected pediatric population.