SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers.,Nature Communications

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SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers.
Nature Communications ( IF 14.7 ) Pub Date : 2017-01-19 , DOI: 10.1038/ncomms14098
Vural Tagal ₁ , Shuguang Wei ₁ , Wei Zhang _{2,

3} , Rolf A Brekken _{3,

4,

5} , Bruce A Posner _{1,

5} , Michael Peyton ₃ , Luc Girard _{3,

4} , TaeHyun Hwang ₆ , David A Wheeler ₇ , John D Minna _{3,

4,

5,

8} , Michael A White _{5,

9} , Adi F Gazdar _{2,

3,

5} , Michael G Roth _{1,

5}

Affiliation

Mutations in the SMARCA4/BRG1 gene resulting in complete loss of its protein (BRG1) occur frequently in non-small cell lung cancer (NSCLC) cells. Currently, no single therapeutic agent has been identified as synthetically lethal with SMARCA4/BRG1 loss. We identify AURKA activity as essential in NSCLC cells lacking SMARCA4/BRG1. In these cells, RNAi-mediated depletion or chemical inhibition of AURKA induces apoptosis and cell death in vitro and in xenograft mouse models. Disc large homologue-associated protein 5 (HURP/DLGAP5), required for AURKA-dependent, centrosome-independent mitotic spindle assembly is essential for the survival and proliferation of SMARCA4/BRG1 mutant but not of SMARCA4/BRG1 wild-type cells. AURKA inhibitors may provide a therapeutic strategy for biomarker-driven clinical studies to treat the NSCLCs harbouring SMARCA4/BRG1-inactivating mutations.

中文翻译：

SMARCA4 失活突变增加非小细胞肺癌对极光激酶 A 抑制剂 VX-680 的敏感性。

SMARCA4/BRG1 基因突变导致其蛋白 (BRG1) 完全丧失，这种情况在非小细胞肺癌 (NSCLC) 细胞中经常发生。目前，还没有任何一种治疗药物被确定为因 SMARCA4/BRG1 缺失而具有综合致死性。我们确定 AURKA 活性对于缺乏 SMARCA4/BRG1 的 NSCLC 细胞至关重要。在这些细胞中，RNAi 介导的 AURKA 消耗或化学抑制可在体外和异种移植小鼠模型中诱导细胞凋亡和细胞死亡。椎间盘大同源相关蛋白 5 (HURP/DLGAP5) 是 AURKA 依赖性、中心体独立的有丝分裂纺锤体组装所需的，对于 SMARCA4/BRG1 突变体的生存和增殖至关重要，但对于 SMARCA4/BRG1 野生型细胞则不然。 AURKA 抑制剂可以为生物标志物驱动的临床研究提供治疗策略，以治疗携带 SMARCA4/BRG1 失活突变的 NSCLC。

更新日期：2017-01-20

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