Essential role of AKT in tumor cells addicted to FGFR

	Essential role of AKT in tumor cells addicted to FGFR
	Hu Y(胡毅); Hu, Y; Lu, HR; Zhang, JC; Chen, J; Chai, ZF; Zhang, JX;陈俊; Chai ZF(柴之芳)
刊名	ANTI-CANCER DRUGS
	2014
卷号	25 期号:2 页码:183-188
关键词	AKT combination fibroblast growth factor receptor kinase inhibitors pharmacodynamic biomarker
英文摘要	Tumor cells with genetic amplifications or mutations in the fibroblast growth factor receptor (FGFR) family are often addicted to FGFR and heavily dependent on its signaling to survive. Although it is critical to understand which signaling pathway downstream of FGFR plays an essential role to guide the research and development of FGFR inhibitors, it has remained unclear partly because the tool compounds used in the literature also hit many other kinases, making the results difficult to interpret. With the development of a potent FGFR-specific inhibitor, BGJ398, we are now able to dissect various pathways with low drug concentrations to minimize multiple-target effects. Importantly, here, we show that inhibition of FGFR signaling by BGJ398 leads to only transient inhibition of ERK1/2 phosphorylation, whereas the inhibitory effect on AKT phosphorylation is sustainable, indicating that AKT, not ERK as commonly believed, serves as an appropriate pharmacodynamic biomarker for BGJ398. Although AKT inhibition by a pan-PI3K inhibitor alone has almost no effect on cell growth, heterologous expression of myr-AKT, an active form of AKT, rescues BGJ398-mediated suppression of tumor cell proliferation. These results indicate that AKT is an essential component downstream of FGFR. Finally, combination of the FGFR inhibitor BGJ398 with rapamycin significantly inhibits AKT phosphorylation and enhances their antiproliferative effects in FGFR-addicted cells, suggesting an effective combination strategy for clinical development of FGFR inhibitors. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
学科主题	Oncology; Pharmacology & Pharmacy
收录类别	SCI
WOS记录号	WOS:000329876400006
公开日期	2016-05-03
内容类型	期刊论文
源URL	[http://ir.ihep.ac.cn/handle/311005/224814]
专题	高能物理研究所_院士
推荐引用方式 GB/T 7714	Hu Y,Hu, Y,Lu, HR,et al. Essential role of AKT in tumor cells addicted to FGFR[J]. ANTI-CANCER DRUGS,2014,25(2):183-188.
APA	胡毅.,Hu, Y.,Lu, HR.,Zhang, JC.,Chen, J.,...&柴之芳.(2014).Essential role of AKT in tumor cells addicted to FGFR.ANTI-CANCER DRUGS,25(2),183-188.
MLA	胡毅,et al."Essential role of AKT in tumor cells addicted to FGFR".ANTI-CANCER DRUGS 25.2(2014):183-188.