Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer
Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer
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DOI：
10.1172/jci.insight.126117
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发表时间：
2019-05-02
期刊：
影响因子：
8
通讯作者：
Brekken, Rolf A.
中科院分区：
文献类型：
--
作者：
Cruz, Victoria H.;Amer, Emily N.;Brekken, Rolf A.
胰腺导管腺癌（PDA）以KRAS的激活突变为特征，通过药物手段直接抑制KRAS仍然是一个挑战；然而，靶向关键的KRAS效应物具有治疗潜力。我们研究了坦克结合激酶1 （TBK1）对PDA进展的贡献，TBK1是突变型活性KRAS的关键下游效应物。我们报道TBK1通过驱动肿瘤细胞中的上皮可塑性程序来支持kras突变PDA的生长和转移，从而增强侵袭和转移能力。此外，我们发现酪氨酸激酶Axl受体以ras - ralb依赖的方式诱导TBK1活性。这些发现表明TBK1是KRAS突变型PDA中Axl驱动的上皮-间质转化的核心，并表明中断KRAS上下的Axl/TBK1信号级联对这种顽固性疾病具有潜在的治疗效果。
Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS, Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. We report that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner. These findings demonstrate that TBK1 is central to an Axl-driven epithelial-mesenchymal transition in KRAS-mutant PDA and suggest that interruption of the Axl/TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.