Detection of Genes Modifying Sensitivity to Proteasome Inhibitors Using a shRNA Library in Breast Cancer
Abstract
The application of RNAi has transformed the way we approach mammalian cell genetics. Over the past year we have made significant progress in several areas that have enhanced the use of shRNAs as a tool for genetic screens. Our second-generation shRNA retroviral library now covers 32,2O2 genes (86,I28 clones) for human and 3O,629 genes (76,896 clones) for mouse genomes. These shRNA can be delivered into cells both in vitro and in vivo using our optimized viral expression vectors. More importantly with these tools we have successfully demonstrated the feasibility of performing genetic screens in mouse and human cells through our pilot efforts. Using the `synthetic-lethal genetic approach we can now perform drug-induced synthetic-lethal screens by using cancer drugs that are currently in clinical trials. This is important as cancer cells can often become resistant to the toxic effects of chemotherapeutics. Bortezomib (Velcade) is the first targeted therapeutic to the proteasome approved by the FDA for treatment against multiple myeloma and is currently in phase II clinical trials for breast and lung cancers. Our goal is to identify genes that mediate resistance against Velcade that could serve as potential drug targets. RNAi technology is a powerful tool that could potentially be used to study and treat other human diseases through its application to mammalian cell genetics.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2007
- Accession Number
- ADA468539
Entities
People
- Gregory Hannon
Organizations
- Cold Spring Harbor Laboratory