期刊
CANCER LETTERS
卷 496, 期 -, 页码 84-92出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2020.09.027
关键词
Cancer/mutation/tyrosine kinase receptor/VEGFR2
类别
资金
- AIRC [IG17276, 23116]
- FIRC Fellowships
- FUV Fellowship
- Fondazione Cariplo
- Regione Lombardia
Mutations in certain tyrosine kinase receptors, such as VEGFR2, can increase enzymatic activity and tumorigenic potential of cancer cells, as well as enhance the sensitivity to specific targeted inhibitors. These findings suggest that screening for such mutations may help predict patient prognosis and drug response in cancer therapy.
In cancer genomics, recurrence of mutations in gene families that share homologous domains has recently emerged as a reliable indicator of functional impact and can be exploited to reveal the pro-oncogenic effect of previously uncharacterized variants. Pan-cancer analyses of mutation hotspots in the catalytic domain of a subset of tyrosine kinase receptors revealed that two infrequent mutations of VEGFR2 (R1051Q and D1052N) recur in analogous proteins and correlate with reduced patient survival. Functional validation showed that both R1051Q and D1052N mutations increase the enzymatic activity of VEGFR2. The expression of VEGFR2R1051Q potentiates the PI3K/Akt signaling axis in cancer cells, increasing their tumorigenic potential in vitro and in vivo. In addition, it confers to cancer cells an increased sensitivity to the VEGFR2-targeted tyrosine kinase inhibitor Linifanib. In the context of an efficacious application of anti-cancer targeted therapies, these findings indicate that the screening for uncharacterized mutations, like VEGFR2(R1051Q), may help to predict patient prognosis and drug response, with significant clinical implications.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据