中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 药理学第一研究室
Integration of Receptor Tyrosine Kinases Determines Sensitivity to PI3K alpha-selective Inhibitors in Breast Cancer

文献类型：期刊论文

作者Xu, Yi-chao1,2; Wang, Xiang1; Chen, Yi1; Chen, Si-meng1; Yang, Xin-ying1; Sun, Yi-ming1; Geng, Mei-yu1; Ding, Jian1,2; Meng, Ling-hua1,2
刊名THERANOSTICS
出版日期2017
卷号7期号:4页码:974-986
关键词BYL719 PI3K ERK receptor tyrosine kinase breast cancer predictive biomarker
ISSN号1838-7640
DOI10.7150/thno.17830
文献子类Article
英文摘要PI3Ka-selective inhibitor BYL719 is currently in phase II/III clinical trial for the treatment of breast cancer, but highly variable response has been observed among patients. We sought to discover predictive biomarker for the efficacy of BYL719 by dissecting the proliferative signaling pathway mediated by PI3K in breast cancer. BYL719 concurrently inhibited the phosphorylation of AKT and ERK in PIK3CA-mutated human breast cancer cells. PI3K-regulated ERK phosphorylation was independent of canonical PDK1/AKT/mTOR pathway, while it was associated with RAF/MEK. Hyper-activation of EGFR or RAS abrogated inhibition of ERK phosphorylation by BYL719. Furthermore, hyper-activation of receptor tyrosine kinases (RTKs) including EGFR, c-MET, FGFR and HER3 but not IGF-1R restored ERK phosphorylation and cell viability suppressed by BYL719, suggesting the discriminative functions of RTKs in cell signaling and proliferation. By profiling 22 breast cancer cell lines, we found that BYL719 was more potent in cell lines where phosphorylation of both AKT and ERK was attenuated than those where only AKT phosphorylation was inhibited. The potency of BYL719 was further found to be significantly correlated with the expression profile of RTKs in breast cancer cells. Specifically, overexpression of EGFR, c-MET and/or FGFR1 forecasted resistance, while overexpression of IGF-1R and/or HER2 predicted sensitivity to BYL719 in breast cancer cells. Similar correlation between BYL719 efficacy and expression profile of RTKs was found in patient-derived xenograft models of breast cancer. Thus, inhibition of ERK phosphorylation by PI3Ka inhibitor BYL719 contributes to its antitumor efficacy and is determined by the converged signaling from RTKs. The expression profile of RTKs in breast cancer tissue could be potentially developed as a predictive biomarker for the efficacy of PI3Ka inhibitors.
WOS关键词PI3K INHIBITORS ; AKT INHIBITOR ; UP-REGULATION ; ACTIVATION ; CELLS ; APOPTOSIS ; RAPAMYCIN ; MUTANT
资助项目National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09301-001] ; National Natural Science Foundation of China[81321092] ; National Natural Science Foundation of China[81373445] ; National Natural Science Foundation of China[81402972] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020202]
WOS研究方向Research & Experimental Medicine
语种英语
WOS记录号WOS:000396559600015
出版者IVYSPRING INT PUBL
源URL[http://119.78.100.183/handle/2S10ELR8/275727]  
专题药理学第一研究室
通讯作者Ding, Jian; Meng, Ling-hua
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai, Peoples R China;
2.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Yi-chao,Wang, Xiang,Chen, Yi,et al. Integration of Receptor Tyrosine Kinases Determines Sensitivity to PI3K alpha-selective Inhibitors in Breast Cancer[J]. THERANOSTICS,2017,7(4):974-986.
APA Xu, Yi-chao.,Wang, Xiang.,Chen, Yi.,Chen, Si-meng.,Yang, Xin-ying.,...&Meng, Ling-hua.(2017).Integration of Receptor Tyrosine Kinases Determines Sensitivity to PI3K alpha-selective Inhibitors in Breast Cancer.THERANOSTICS,7(4),974-986.
MLA Xu, Yi-chao,et al."Integration of Receptor Tyrosine Kinases Determines Sensitivity to PI3K alpha-selective Inhibitors in Breast Cancer".THERANOSTICS 7.4(2017):974-986.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。