A framework for identification of actionable cancer genome dependencies in small cell lung cancer
A framework for identification of actionable cancer genome dependencies in small cell lung cancer
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DOI：
10.1073/pnas.1207310109
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发表时间：
2012-10-16
影响因子：
11.1
通讯作者：
Thomas, Roman K.
中科院分区：
文献类型：
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作者：
Sos, Martin L.;Dietlein, Felix;Thomas, Roman K.
小细胞肺癌(SCLC)约占所有肺癌的15%。小细胞肺癌患者的预后是毁灭性的，这种肿瘤类型没有有效的生物靶向治疗药物。为了开发特定的小细胞肺癌靶向药物的框架，我们在小细胞肺癌细胞系中进行了基因组和药理学联合易损性筛查。我们通过在44个SCLC细胞系中筛选267个化合物，证明了SCLC细胞系捕捉到了原发SCLC肿瘤的基因组图谱，并为临床相关抑制物的活性提供了遗传预测因子。我们发现Aurora激酶抑制剂对携带MYC扩增的SCLC细胞株有效，这种扩增发生在3-7%的SCLC患者中。在MYC扩增的SCLC细胞中，Aurora激酶抑制与G2/M期阻滞、PI3K信号失活和诱导细胞凋亡有关。小细胞肺癌对Aurora的依赖主要涉及Aurora B，需要它的激酶活性，并且不依赖于MYC胞浆水平的耗竭。我们的研究表明，一小部分小细胞肺癌患者可能受益于对Aurora B的治疗抑制。因此，对小细胞肺癌细胞系的彻底化学和基因组探索可能为进一步开发合理的靶向治疗这种致命肿瘤类型提供起点。
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3-7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.