| Title | An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors |
|---|---|
| Published in | Nature chemical biology, Vol. 2, p.202-206. ISSN 1552-4450. |
| Author | Bernards, R.A.; Brummelkamp, T.R.; Fabius, A.W.M.; Mullenders, J.; Madiredjo, M.; Velds, A.; Kerkhoven, R.M.; Beijersbergen, R.L. |
| Date | 2006-04 |
| Language | English |
| Type | article |
| Publisher | Nature Publishing Group |
| Abstract | The identification of the cellular targets of small molecules with anticancer activity is crucial to their further development as drug candidates. Here, we present the application of a large-scale RNA interference–based short hairpin RNA (shRNA) barcode screen to gain insight in the mechanism of action of nutlin-3. Nutlin-3 is a small-molecule inhibitor of MDM2, which can activate the p53 pathway. Nutlin-3 shows strong antitumor effects in mice, with surprisingly few side effects on normal tissues1. Aside from p53, we here identify 53BP1 as a critical mediator of nutlin-3–induced cytotoxicity. 53BP1 is part of a signaling network induced by DNA damage that is frequently activated in cancer but not in healthy tissues. Our results suggest that nutlin-3's tumor specificity may result from its ability to turn a cancer cell–specific property (activated DNA damage signaling) into a weakness that can be exploited therapeutically. |
| Publication | http://igitur-archive.library.uu.nl/bio/2007-0502-200259/UUi... |
| Persistent Identifier | URN:NBN:NL:UI:10-1874-21014 |
| Metadata | XML |
| Repository | Utrecht University |
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