Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress
Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress
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DOI：
10.1073/pnas.1105941108
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发表时间：
2011-05-24
影响因子：
11.1
通讯作者：
Jacks, Tyler
中科院分区：
文献类型：
--
作者：
Shaw, Alice T.;Winslow, Monte M.;Jacks, Tyler
激活K-RAS突变是人类癌症中最常见的致癌突变。许多下游信号通路已被证明是由致癌K-ras的失调。然而，迄今为止，仍然没有针对这种基因定义的患者子集的有效靶向治疗。在这里，我们报告的结果，小分子，合成的致死屏幕使用小鼠胚胎成纤维细胞来源于小鼠模型窝藏条件致癌K-ras（G12 D）等位基因。在筛选的> 50，000种化合物中，我们鉴定了一类对致癌K-ras表达细胞具有选择性活性的药物。这类药物中最有效的药物是兰哌立松，其作用是以细胞周期和凋亡独立的方式诱导非凋亡性细胞死亡。细胞杀伤的机制涉及诱导活性氧，这些活性氧在K-ras突变细胞中被无效清除，导致氧化应激和细胞死亡。在小鼠中，用兰哌立松治疗抑制K-ras驱动的肿瘤的生长，而没有明显的毒性。我们的研究结果确立了兰哌立松的特异性抗肿瘤活性，并揭示了氧化应激途径作为Ras介导的恶性肿瘤的潜在靶点。
Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic K-ras(G12D) allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras-expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle-and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras-driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras-mediated malignancies.