Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
Cancer Cell. 2012 Sep 11;22(3):304-17. doi: 10.1016/j.ccr.2012.07.024.
Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
胰腺导管腺癌（PDA）的发生与 KRAS 癌基因的激活突变密切相关。然而，PDA 小鼠模型表明，早期发育中突变 Kras 的表达会导致正常的胰腺，只有在长时间的潜伏期或胰腺炎诱导后才会形成肿瘤。在这里，我们表明致癌 KRAS 上调内源性 EGFR 的表达和激活，后者依赖于 EGFR 配体脱落酶 ADAM17。EGFR 或 ADAM17 的遗传缺失或药理学抑制可有效消除体内 KRAS 驱动的肿瘤发生。没有 EGFR 活性，活性 RAS 水平不足以诱导强烈的 MEK/ERK 活性，这是上皮转化的必需条件。
