NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma
NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma
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DOI：
10.1016/j.ccr.2012.02.008
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发表时间：
2012-03-20
期刊：
影响因子：
50.3
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
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作者：
Yamaguchi, Tomoya;Yanagisawa, Kiyoshi;Takahashi, Takashi
我们和其他人以前确定NKX 2 -1，也称为TITF 1和TTF-1，是肺腺癌中的谱系存活癌基因。在这里，我们表明NKX 2 -1诱导受体酪氨酸激酶样孤儿受体1（ROR 1）的表达，这反过来又维持了促生存PI 3 K-AKT和促凋亡p38信号传导之间的良好平衡，部分通过ROR 1激酶依赖性c-Src激活，以及EGFR-ERBB 3结合、ERBB 3磷酸化和相应的PI 3 K激活的激酶活性非依赖性维持。值得注意的是，ROR 1敲低有效抑制肺腺癌细胞系，无论其EGFR状态如何，包括对EGFR酪氨酸激酶抑制剂吉非替尼具有抗性的那些。因此，我们的研究结果将ROR 1确定为肺腺癌中的“阿喀琉斯之踵”，从而阻碍了这种毁灭性癌症治疗策略的未来发展。
We and others previously identified NKX2-1, also known as TITF1 and TTF-1, as a lineage-survival oncogene in lung adenocarcinomas. Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines, irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Our findings thus identify ROR1 as an "Achilles' heel" in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer.