A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma.
A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma.
复制标题
DOI：
10.1158/0008-5472.can-14-2004
复制
发表时间：
2015-01-15
期刊：
影响因子：
11.2
通讯作者：
Furnari FB
中科院分区：
文献类型：
--
作者：
Wykosky J;Hu J;Gomez GG;Taylor T;Villa GR;Pizzo D;VandenBerg SR;Thorne AH;Chen CC;Mischel PS;Gonias SL;Cavenee WK;Furnari FB
EGFR是胶质母细胞瘤(GBM)中最常见的基因改变癌基因，但小分子EGFR酪氨酸激酶抑制剂(TKIs)未能产生持久的临床疗效。在这里，我们证明了在两个新的对EGFR TKI获得性耐药的模型系统中，尿激酶型纤溶酶原激活物(UPA)的高表达通过MAPK途径驱动信号传递，从而导致促凋亡的BCL2家族成员蛋白BIM(BCL2L11)的抑制。在患者来源的GBM细胞和遗传的GBM模型中，uPA被证明通过ERK1/2磷酸化抑制BIM水平，这种作用可以被siRNA介导的uPA下调所逆转。通过药物抑制MEK或BH3模拟药物来替代BIM功能，对TKI耐药的GBM重新对EGFR TKI敏感。UPA-uPAR-ERK1/2通路与BIM之间的联系以前在GBM中还没有被证明，这个信号轴参与耐药为针对EGFR TKI耐药的GBM的新策略提供了理论基础。
EGFR is the most common genetically altered oncogene in glioblastoma (GBM), but small molecule EGFR tyrosine kinase inhibitors (TKIs) have failed to yield durable clinical benefit. Here we show that in two novel model systems of acquired resistance to EGFR TKIs, elevated expression of urokinase plasminogen activator (uPA) drives signaling through the MAPK pathway, which results in suppression of the pro-apoptotic BCL2-family member protein BIM (BCL2L11). In patient-derived GBM cells and genetic GBM models uPA is shown to suppress BIM levels through ERK1/2 phosphorylation, which can be reversed by siRNA mediated knockdown of uPA. TKI-resistant GBMs are re-sensitized to EGFR TKIs by pharmacological inhibition of MEK or a BH3 mimetic drug to replace BIM function. A link between the uPA-uPAR-ERK1/2 pathway and BIM has not been previously demonstrated in GBM, and involvement of this signaling axis in resistance provides rationale for a new strategy to target EGFR TKI-resistant GBM.