CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib.
CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib.
复制标题
小细胞肺癌中的 CHK1 抑制可在生物标志物定义的疾病亚群中产生单药活性，以及与顺铂或奥拉帕尼的联合活性。
DOI：
10.1158/0008-5472.can-16-3409
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发表时间：
2017-07-15
期刊：
影响因子：
11.2
通讯作者：
Byers LA
中科院分区：
文献类型：
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作者：
Sen T;Tong P;Stewart CA;Cristea S;Valliani A;Shames DS;Redwood AB;Fan YH;Li L;Glisson BS;Minna JD;Sage J;Gibbons DL;Piwnica-Worms H;Heymach JV;Wang J;Byers LA
小细胞肺癌（SCLC）是最具侵袭性的肺癌，仍然迫切需要有效的靶向治疗。在这里，我们报告了通过针对 SCLC 中过度表达的细胞周期检查点激酶 CHK1 所引发的临床前疗效的证据。我们的研究采用了 RNAi 介导的衰减或药理学阻断与新型第二代 CHK1 抑制剂 prexasertib (LY2606368)，目前正在进行临床试验。在SCLC体外和体内模型中，LY2606368表现出强大的单药疗效，增强了顺铂或PARP抑制剂奥拉帕尼的作用，并改善了铂类耐药模型的反应。蛋白质组学分析确定 CHK1 和 MYC 是 LY2606368 敏感性的首要预测生物标志物，表明 CHK1 抑制可能对伴有 MYC 扩增或 MYC 蛋白过表达的 SCLC 特别有效。我们的研究结果提供了临床前概念证明，支持在铂类敏感或铂类耐药复发性 SCLC 患者中启动临床疗效试验。
Effective targeted therapies for small-cell lung cancer (SCLC), the most aggressive form of lung cancer, remain urgently needed. Here we report evidence of preclinical efficacy evoked by targeting the overexpressed cell-cycle checkpoint kinase CHK1 in SCLC. Our studies employed RNAi-mediated attenuation or pharmacologic blockade with the novel second-generation CHK1 inhibitor prexasertib (LY2606368), currently in clinical trials. In SCLC models in vitro and in vivo, LY2606368 exhibited strong single-agent efficacy, augmented the effects of cisplatin or the PARP inhibitor olaparib, and improved the response of platinum-resistant models. Proteomic analysis identified CHK1 and MYC as top predictive biomarkers of LY2606368 sensitivity, suggesting that CHK1 inhibition may be especially effective in SCLC with MYC amplification or MYC protein overexpression. Our findings provide a preclinical proof of concept supporting the initiation of a clinical efficacy trial in patients with platinum-sensitive or platinum-resistant relapsed SCLC.