A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma.
A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma.
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DOI：
10.1158/2159-8290.cd-11-0347
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发表时间：
2012-08
期刊：
影响因子：
28.2
通讯作者：
McMahon M
中科院分区：
文献类型：
--
作者：
Collisson EA;Trejo CL;Silva JM;Gu S;Korkola JE;Heiser LM;Charles RP;Rabinovich BA;Hann B;Dankort D;Spellman PT;Phillips WA;Gray JW;McMahon M
KRAS突变是胰腺导管腺癌(PDA)的一个特征，但仍是一个难以处理的药理靶点。因此，明确动脉导管未闭的启动和维持所需的RAS效应通路(S)对于改善该病的治疗至关重要。在这里，我们证明了BRAFV600E，而不是PIK3CAH1047R，在小鼠胰腺中的表达会导致胰腺上皮内瘤变(Panin)病变。此外，BRAFV600E和TP53R270H的同时表达导致致死性PDA。我们测试了RAS效应器的药物抑制剂对多个人PDA细胞株的作用。MEK抑制作用在体内和体外都很有效，并且与AKT抑制作用在大多数细胞系中具有协同作用。我们证明RAF-→-MEK-→-ERK信号转导通路在动脉导管未闭的启动和维持以及合理的联合治疗策略中起着中心作用。这些结果强调了利用多个互补的实验系统来确定PDA有效干预策略的优先路径的价值。
KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA), but remains an intractable pharmacological target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance is critical to improve treatment of this disease. Here we demonstrate that expression of BRAFV600E, but not PIK3CAH1047R, in the mouse pancreas leads to pancreatic intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant expression of BRAFV600E and TP53R270H result in lethal PDA. We tested pharmacologic inhibitors of Ras effectors against multiple human PDA cell lines. MEK inhibition was highly effective both in vivo and in vitro, and was synergistic with AKT inhibition in most cell lines tested. We demonstrate that RAF→MEK→ERK signaling is central to the initiation and maintenance of PDA and to rational combination strategies in this disease. These results emphasize the value of leveraging multiple complementary experimental systems to prioritize pathways for effective intervention strategies in PDA.