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Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy

2006; National Academy of Sciences; Volume: 103; Issue: 6 Linguagem: Inglês

10.1073/pnas.0507493103

1091-6490

Christian Tovar, James Rosinski, Zoran Filipovic, Brian Higgins, Kenneth Kolinsky, Holly Hilton, Xiaolan Zhao, Binh Thanh Vu, Weiguo Qing, Kathryn Packman, Ola Myklebost, David Heimbrook, Lyubomir T. Vassilev,

Epigenetics and DNA Methylation

The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53-MDM2 interaction.