EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma.
EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma.
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DOI：
10.1016/j.ccr.2012.08.001
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发表时间：
2012-09-11
期刊：
影响因子：
50.3
通讯作者：
Barbacid M
中科院分区：
文献类型：
--
作者：
Navas C;Hernández-Porras I;Schuhmacher AJ;Sibilia M;Guerra C;Barbacid M
临床证据表明，表皮生长因子受体（EGFR）的突变/激活与肺和结肠肿瘤中K-RAS癌基因的存在是相互排斥的。我们已经使用基因工程小鼠模型验证了这些观察结果。然而，由K-Ras癌基因驱动的胰腺导管腺癌完全依赖于EGFR信号传导。使用人胰腺肿瘤细胞系获得了类似的结果。即使在胰腺损伤和p16 Ink 4a/p19 Arf缺失的情况下，EGFR也是必需的。只有p53的缺失使得胰腺肿瘤不依赖于EGFR信号传导。PI 3 K和STAT 3的额外抑制有效地防止了源自这些p53缺陷胰腺肿瘤的外植体的增殖。这些结果可能为临床上更合理地治疗胰腺肿瘤提供依据。
Clinical evidence indicates that mutation/activation of EGF receptors (EGFRs) is mutually exclusive with the presence of K-RAS oncogenes in lung and colon tumors. We have validated these observations using genetically engineered mouse models. However, pancreatic ductal adenocarcinomas driven by K-Ras oncogenes are totally dependent on EGFR signaling. Similar results were obtained using human pancreatic tumor cell lines. EGFRs were also essential even in the context of pancreatic injury and absence of p16Ink4a/p19Arf. Only loss of p53 made pancreatic tumors independent of EGFR signaling. Additional inhibition of PI3K and STAT3 effectively prevented proliferation of explants derived from these p53–defective pancreatic tumors. These findings may provide the bases for more rational approaches to treat pancreatic tumors in the clinic.
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