A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer
A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer
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使用 YAP 和泛 RAF 抑制剂治疗 KRAS 突变胰腺癌的组合策略
DOI：
10.1016/j.canlet.2017.05.015
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发表时间：
2017-08-28
期刊：
影响因子：
9.7
通讯作者：
Nie, Guangjun
中科院分区：
文献类型：
--
作者：
Zhao, Xiao;Wang, Xiuchao;Nie, Guangjun
KRAS突变是胰腺癌中最常见的遗传事件。虽然KRAS本身已被证明难以抑制，但靶向KRAS关键下游信号的药物（如RAF）可能对胰腺癌治疗有效。因为选择性BRAF抑制剂矛盾地诱导下游信号传导激活，所以泛RAF抑制剂LY3009120是KRAS突变肿瘤治疗的更好替代物。在这里，我们探索了一种新的组合策略，使用雅普抑制剂和LY3009120在胰腺癌治疗。我们发现，降低雅普表达与较长的无复发和患者的总生存期密切相关。稳定敲除雅普显著抑制胰腺癌细胞增殖和肿瘤生长。此外，LY3009120与雅普敲低组合表现出显著增强的抗肿瘤作用。LY 3009120处理后，雅普磷酸酶缺失可阻断平行ART信号途径的激活。最后，与雅普抑制剂维替泊芬的组合显著增强了LY 3009120的抗肿瘤功效。总的来说，我们的结果表明，雅普的遗传或药理学抑制可以通过阻断平行AKT信号通路的代偿性激活来增加胰腺癌中对LY3009120的敏感性，从而验证用于治疗KRAS突变型胰腺癌的组合方法。(C)2017爱思唯尔B.V.保留所有权利。
KRAS mutation is the most common genetic event in pancreatic cancer. Whereas KRAS itself has proven difficult to inhibit, agents that target key downstream signals of KRAS, such as RAF, are possibly effective for pancreatic cancer treatment. Because selective BRAF inhibitors paradoxically induce downstream signaling activation, a pan-RAF inhibitor, LY3009120 is a better alternate for KRAS-mutant tumor treatment. Here we explored a new combinational strategy using a YAP inhibitor and LY3009120 in pancreatic cancer treatment. We found that reduced YAP expression closely correlates with longer relapse-free and overall survival of patients. Stable knockdown of YAP significantly inhibited pancreatic cancer cell proliferation and tumor growth. In addition, LY3009120 exhibited a dramatically enhanced antitumor effect in combination with YAP knockdown. YAP depletion blocks the activation of a parallel ART signal pathway after LY3009120 treatment. Finally, combination with a YAP inhibitor, verteporfin, significantly enhanced the antitumor efficacy of LY3009120. Collectively, our results demonstrate that genetic or pharmacological inhibition of YAP can increase sensitivity to LY3009120 in pancreatic cancer through blocking compensatory activation of a parallel AKT signal pathway, thereby validating a combinatorial approach for treating KRAS-mutant pancreatic cancer. (C) 2017 Elsevier B.V. All rights reserved.