Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer

doi:10.1007/s00109-010-0635-0

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer
	Chen, Guang ; Yang, Na ; Wang, Xiang ; Zheng, Si-Yuan 2; Chen, Yi1 ; Tong, Lin-Jiang ; Li, Yi-Xue 2; Meng, Ling-Hua; Ding, Jian
刊名	JOURNAL OF MOLECULAR MEDICINE-JMM
	2010-09
卷号	88 期号:9 页码:941-952
关键词	mTOR Biomarker p27 Rapamycin Rapalogs Cancer
ISSN号	0946-2716
DOI	10.1007/s00109-010-0635-0
文献子类	Article
英文摘要	Rapamycin analogs temsirolimus and everolimus have been approved for the treatment of advanced renal cancer and are being tested in a wide spectrum of human tumors. However, objective response rates with rapalogs in clinical trials were modest and variable. Identification of biomarkers capable of predicting response to rapalogs is of increasing interest. We analyzed pairwise Pearson correlation coefficients (r) between rapalogs activity and gene expression profile for each NCI-60 cell line. p27 showed the highest positive correlation among 9,706 gene probes tested. At cellular levels, breast cancer MCF-7, T47D, and BT-474 cells, expressing high levels of p27, were sensitive to rapalogs, whereas the cells expressed low levels of p27, such as MDA-MB-231, MDA-MB-468, and MDA-MB-435 cells, exhibited resistance to rapalogs. Mechanistic study indicated that this correlation is likely determined by the basal level of p27 regardless of the phosphorylation or redistribution of p27 upon rapalogs treatment, which may provide a putative threshold to block G1/S transition. Consistently, down-regulation of p27 by siRNA conferred MCF-7 and BT-474 cells insensitive to rapalogs. Moreover, a significant positive correlation between p27 gene expression and rapamycin anti-tumor activity was also observed in mice bearing different human cancer cell xenografts. In conclusion, p27 expression level is positively correlated with the anticancer activity of rapalogs in vitro and in vivo. We propose p27 expression level may be also a candidate predictive biomarker for patient selection for rapalogsbased therapy, which requires clinical validation in a series of patients treated with rapalogs.
资助项目	National Science & Technology Major Project[2009ZX09301-001] ; National Science & Technology Major Project[2009ZX09102-025] ; National Natural Science Foundation of China[30721005] ; Science and Technology Commission of Shanghai Municipality Pujiang Talent Program[08PJ14114] ; Science and Technology Commission of Shanghai Municipality Pujiang Talent Program[07dz05906] ; Science and Technology Commission of Shanghai Municipality Pujiang Talent Program[074319113-2]
WOS关键词	RECURRENT GLIOBLASTOMA-MULTIFORME ; RENAL-CELL CARCINOMA ; PHASE-II TRIAL ; BREAST-CANCER ; TEMSIROLIMUS CCI-779 ; INHIBITOR P27 ; DETERMINES SENSITIVITY ; ENHANCED SENSITIVITY ; RAD001 EVEROLIMUS ; MAMMALIAN TARGET
WOS研究方向	Genetics & Heredity ; Research & Experimental Medicine
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000280918800010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278788]
专题	药理学第一研究室
通讯作者	Meng, Ling-Hua
作者单位	1.Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang 110016, Liaoning, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Biol Sci, Bioinformat Ctr, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Chen, Guang,Yang, Na,Wang, Xiang,et al. Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer[J]. JOURNAL OF MOLECULAR MEDICINE-JMM,2010,88(9):941-952.
APA	Chen, Guang.,Yang, Na.,Wang, Xiang.,Zheng, Si-Yuan.,Chen, Yi.,...&Ding, Jian.(2010).Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer.JOURNAL OF MOLECULAR MEDICINE-JMM,88(9),941-952.
MLA	Chen, Guang,et al."Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer".JOURNAL OF MOLECULAR MEDICINE-JMM 88.9(2010):941-952.