The role of KRAS, when activated through canonical mutations, has been well established in cancer¹. Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas^2-4. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.

中文翻译：

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通过联合MEK和SHP2抑制作用靶向野生型KRAS扩增的胃食管癌。

当通过典型突变激活时，KRAS的作用已在癌症中得到了很好的证实¹。在这里，我们探讨了癌症中KRAS激活的第二种方法：在不存在编码突变的情况下，对KRAS基因进行局灶性高水平扩增。这些扩增最常见于食道，胃和卵巢腺癌^2-4。KRAS扩增的胃癌模型显示出KRAS蛋白的明显过表达，并且由于其能够通过迅速增加的KRAS-GTP水平进行自适应反应的能力而对MAPK阻滞不敏感。在这里，我们证明抑制鸟嘌呤交换因子SOS1和SOS2或蛋白酪氨酸磷酸酶SHP2可以减弱这种适应性过程，并且针对这些因子，无论是从遗传学还是从药理学方面，都可以增强KRAS扩增模型对MEK抑制的敏感性体外和体内设置。这些数据证明了拷贝数扩增作为KRAS激活机制的相关性，并揭示了通过结合SHP2和MEK抑制作用靶向这些肿瘤的治疗潜力。