Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies
Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies
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DOI：
10.1002/mc.22476
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发表时间：
2017-01-01
影响因子：
4.6
通讯作者：
Nishio, Kazuto
中科院分区：
文献类型：
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作者：
Mizukami, Takuro;Togashi, Yosuke;Nishio, Kazuto
尽管成纤维细胞生长因子（FGF）信号与恶性肿瘤密切相关，但关于FGF9信号在结直肠癌（CRC）中的作用的信息有限。在本研究中，我们研究了FGF9在结直肠癌临床标本中的扩增频率，以及FGF9基因与抗egfr治疗耐药性之间的关系。在临床样本中，FGF9拷贝数增加5个拷贝的频率为8/145(5.5%)，可能与野生型KRAS有关（7/96,7.3%）。此外，在抗egfr治疗的15例应答者的样本中未观察到FGF9扩增，但在7例野生型KRAS无应答者的一个样本中观察到FGF9扩增，并且来自无应答者的两个样本也具有高FGF9 mRNA表达水平。使用荧光原位杂交（FISH）分析验证了FGF9扩增，并且在免疫组织化学检查时，FGF9扩增的切片显示容易检测到源自FGF9蛋白的信号。在体外和体内使用过表达FGF9的CRC细胞系进行的实验中，FGF9过表达通过增强的FGFR信号诱导了对抗egfr治疗的强烈耐药性，这种耐药性被FGFR抑制剂的应用所消除。考虑到这些结果，FGF9基因可能在结直肠癌患者对抗egfr治疗的耐药中发挥重要作用，并且这种耐药可能通过与抗fgfr抑制剂联合治疗来克服。这些发现强烈鼓励fgfr靶向治疗FGF9基因上调的结直肠癌患者。(c) 2016 Wiley Periodicals, Inc.；
Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of 5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. (c) 2016 Wiley Periodicals, Inc.