期刊
BIOCHEMICAL JOURNAL
卷 417, 期 -, 页码 361-370出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20081682
关键词
chemical screen; phosphoinositide-dependent kinase 1 (PDK1); RNA interference screen; tamoxifen; tetrandrine; triciribine
资金
- Tertiary Education Commission of NewZealand [BBC 024]
Tamoxifen is the most commonly used drug to treat breast cancer and acts by blocking ER alpha (oestrogen receptor (alpha) signalling. Although highly effective, its usefulness is limited by the development of resistance. Given this, strategies that limit resistance by sensitizing cells to tamoxifen may be of use in the clinic. To gain insight into how this might be achieved, We used Chemical and genetic screens to identify targets and small-molecule inhibitors that Cause tamoxifen sensitization. A high-throughput genetic Screen, using an RNA interference library targeting 779 kinases and related proteins, identified the PDK1 (phosphoinositide-dependent kinase 1) signalling pathway as It strong determinant of sensitivity to Multiple ER alpha antagonists, including tamoxifen. A chemical screen using existing drugs and known kinase inhibitors also identified inhibitors of the PDK1 pathway, including triciribine and tetrandrine. Aside from identifying novel agents and targets for tamoxifen sensitization, this approach also provides evidence that performing chemical and genetic screens in parallel may be useful.
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