Parallel RNAi and compound screens identify the PDK1 pathway as a target for tamoxifen sensitization.
Date
2009-01Author
Iorns, E
Lord, CJ
Ashworth, A
Type
Journal Article
Metadata
Show full item recordAbstract
Tamoxifen is the most commonly used drug to treat breast cancer and acts by blocking ERalpha (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 a strong determinant of sensitivity to multiple ERalpha 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.
Collections
Subject
Cell Line, Tumor
Humans
Tamoxifen
Benzylisoquinolines
Estrogen Antagonists
Protein-Serine-Threonine Kinases
Ribonucleosides
Flow Cytometry
Signal Transduction
Cell Survival
RNA Interference
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Research team
Gene Function
Language
eng
License start date
2009-01
Citation
The Biochemical journal, 2009, 417 (1), pp. 361 - 370