Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation
Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation
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DOI：
10.1158/0008-5472.can-08-0770
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Pollock, Pamela M.
中科院分区：
文献类型：
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作者：
Byron, Sara A.;Gartside, Michael G.;Pollock, Pamela M.
KRAS激活和PTEN失活是子宫内膜肿瘤发生中的常见事件，分别发生在10% ~ 30%和26% ~ 80%的子宫内膜癌中。由于我们最近在16%的子宫内膜样子宫内膜癌中发现了成纤维细胞生长因子受体2 （FGFR2）的激活突变，因此我们试图确定FGFR2突变发生的遗传背景。对116例原发性子宫内膜样子宫内膜癌的分析显示，FGFR2和KRAS突变是相互排斥的，而FGFR2突变与PTEN突变同时存在。在这里，我们表明shRNA敲低FGFR2或用泛fgfr抑制剂PD173074治疗，导致细胞周期阻滞和诱导子宫内膜癌细胞中FGFR2激活突变的细胞死亡。这种对FGFR2抑制的细胞死亡发生在PTEN和组成型ANT磷酸化的功能丧失突变的背景下，并与细胞外信号调节激酶1/2激活的显著减少相关。总之，这些数据表明，抑制FGFR2可能是FGFR2激活突变的子宫内膜肿瘤的一种可行的治疗选择，尽管PTEN在这种癌症类型中经常被废除。
KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive ANT phosphorylation, and was associated with it marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.