Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Novartis Institutes for Biomedical Research, Inc., Cambridge, MA, USA.
Nat Med. 2018 Jul;24(7):968-977. doi: 10.1038/s41591-018-0022-x. Epub 2018 May 28.
The role of KRAS, when activated through canonical mutations, has been well established in cancer. 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. 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.
KRAS 基因在经典突变激活的情况下在癌症中的作用已得到充分证实。在这里，我们探讨了癌症中 KRAS 激活的第二种方式：KRAS 基因在没有编码突变的情况下发生局灶性高水平扩增。这些扩增最常见于食管、胃和卵巢腺癌中。KRAS 扩增的胃癌模型显示 KRAS 蛋白的明显过表达，并且由于其通过快速增加 KRAS-GTP 水平来适应的能力而对 MAPK 阻断不敏感。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，并且通过遗传和药理学靶向这些因子，可以增强 KRAS 扩增模型对 MEK 抑制的敏感性，无论是在体外还是体内环境中。这些数据表明拷贝数扩增作为 KRAS 激活的机制具有相关性，并揭示了通过联合 SHP2 和 MEK 抑制靶向这些肿瘤的治疗潜力。
